Non nucleoside reverse transcriptase inhibitors

ABSTRACT

Compounds of formula (I): 
                         
wherein Ar, X, R 1 , R 2 , R 3  and R 4  are as defined herein. The compounds are useful as reverse transcriptase inhibitors against wild type and single or double mutant strains of HIV.

TECHNICAL FIELD OF THE INVENTION

The invention relates to novel compounds which inhibit HIV reversetranscriptase, a method for the treatment of HIV infection using suchcompounds, and to pharmaceutical compositions comprising such compounds.

BACKGROUND OF THE INVENTION

The disease known as acquired immune deficiency syndrome (AIDS) iscaused by the human immunodeficiency virus (HIV), particularly thestrain known as HIV-1. In order for HIV to be replicated by a host cell,the information of the viral genome must be integrated into the hostcell's DNA. However, HIV is a retrovirus, meaning that its geneticinformation is in the form of RNA. The HIV replication cycle thereforerequires a step of transcription of the viral genome (RNA) into DNA,which is the reverse of the normal chain of events. An enzyme that hasbeen aptly dubbed reverse transcriptase (RT) accomplishes thetranscription of the viral RNA into DNA. The HIV virion includes copiesof RT along with the viral RNA.

Reverse transcriptase has three known enzymatic functions; it acts as anRNA-dependent DNA polymerase, as a ribonuclease, and as a DNA-dependentDNA polymerase. Acting as an RNA-dependent DNA polymerase, RTtranscribes a single-stranded DNA copy of the viral RNA. Acting as aribonuclease, RT destroys the original viral RNA, and frees the DNA justproduced from the original RNA. Finally, acting as a DNA-dependent DNApolymerase, RT makes a second, complementary DNA strand, using the firstDNA strand as a template. The two strands form double-stranded DNA,which is integrated into the host cell's genome by another enzyme calledintegrase.

Compounds that inhibit the enzymatic functions of HIV-1 reversetranscriptase will inhibit replication of HIV-1 in infected cells. Suchcompounds are useful in the prevention or treatment of HIV-1 infectionin human subjects, as demonstrated by known RT inhibitors such aszidovudine, didanosine, zalcitabine, stavudine, lamivudine,emtricitabine, abacavir, tenofovir, nevirapine, delavirdine andefavirenz, the main reverse transcriptase inhibitors thus far approvedfor use in the treatment of AIDS.

As with any antiviral therapy, use of RT inhibitors in the treatment ofAIDS eventually leads to a virus that is less sensitive to the givendrug. Resistance (reduced sensitivity) to these drugs is the result ofmutations that occur in the reverse transcriptase segment of the polgene. Several mutant strains of HIV have been characterized, andresistance to known therapeutic agents is believed to be due tomutations in the RT gene. One of the more commonly observed mutantsclinically for the non-nucleoside reverse transcriptase inhibitors isthe K103N mutant, in which a lysine (K), at codon 103, has been mutatedto a asparagine (N) residue. Other mutants, which emerge with varyingfrequency during treatment using known antivirals, include singlemutants Y181C, G190A, Y188C, and P236L, and double mutants K103NNY181C,K103N/P225H, K103NN1081 and K103N/L1001.

As antiviral use in therapy and prevention of HIV infection continues,the emergence of new resistant strains is expected to increase. There istherefore an ongoing need for new inhibitors of RT, which have differentpatterns of effectiveness against the various resistant mutants.

Antivirals active against HIV containing a thiadiazolyloxyacetamide orthiadiazolylthioacetamide moiety have been described in JP 07-188017(Soyaku Gijutsu Kenkyusho) and non-nucleoside inhibitors of wild-typeHIV reverse transcriptase containing triazolyl and imidazolyl moietieshave been described in WO 2004/030611 (Ribapharm). The present inventionprovides novel compounds which show potent activity against wild typeHIV reverse transcriptase as well as against single mutant and doublemutant strains.

SUMMARY OF THE INVENTION

The invention provides compounds of formula (I) which are useful fortreating HIV infection in a human infected by HIV. The compounds arepotent inhibitors of wild-type (WT) and double mutant strains of HIV-1RT, particularly the double mutation K103N/Y181C.

In a first aspect the invention provides a compound, represented byformula (I):

wherein

-   Ar is a 5-membered aromatic heterocycle containing 1 to 4    heteroatoms each independently selected from N, O and S; said    heterocycle being optionally substituted at a substitutable position    with RAT, wherein R^(Ar) is H, (C₁₋₄)alkyl, CF₃ or (C₃₋₇)cycloalkyl    and wherein the groups X and R¹ are attached to positions on the Ar    ring which are immediately adjacent to each other;-   X is selected from O and S;-   R¹ is a group of formula:

-   R¹¹ is halo; and-   R¹², R¹³, R¹⁴ and R¹⁵ are each independently selected from H, halo,    (C₁₋₄)alkyl, CF₃, (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-,    cyano, —O—(C₁₋₄)alkyl, —OCF₃ and —N((C₁₋₄)alkyl)₂, wherein said    (C₃₋₇)cycloalkyl is optionally substituted with (C₁₋₄)alkyl; or-   R¹² and R¹³, R¹³ and R¹⁴, or R¹⁴ and R¹⁵ are linked, together with    the carbon atoms to which they are attached, to form a five- or    six-membered saturated, unsaturated or aromatic ring which    optionally contains from one to three heteroatoms each independently    selected from O, S and N, wherein the remaining of R¹², R¹³, R¹⁴ and    R¹⁵ are defined as hereinbefore;-   R² is selected from halo, nitro and (C₁₋₄)alkyl;-   R³ is selected from H and halo;-   R⁴ is selected from:-   a)

wherein R⁴² is bonded to position 2 or position 3 of the phenyl ring andis selected from H, halo and (C₁₋₄)alkyl; and R⁴¹ is bonded to position3 or position 4 of the phenyl ring and is selected from:

-   -   i) (C₁₋₄)alkyl substituted with —COOH, —COO(C₁₋₄)alkyl,        —C(═O)NH₂, —C(═O)NHSO₂—(C₁₋₄)alkyl, or —OH;    -   ii) (C₂₋₄)alkenyl substituted with —COOH or —COO(C₁₋₄)alkyl;    -   iii) —O—(C₁₋₄)alkyl optionally substituted with —COOH, Het, or        —N((C₁₋₆)alkyl)₂, wherein said Het is optionally substituted        with —OH or —COOH and wherein either or both of the (C₁₋₆)alkyl        groups in said —N((C₁₋₆)alkyl)₂ are optionally substituted with        —COOH or —COO(C₁₋₄)alkyl; and    -   iv) —OH, —COOH, —COO(C₁₋₄)alkyl, —SO₂NH₂, or —SO₂-(C₁₋₄)alkyl;    -   provided that R⁴² and R⁴¹ may not both be bonded to position 3        of the phenyl ring at the same time;

-   b) (C₂₋₄)alkenyl substituted with —COOH or —COO(C₁₋₄)alkyl;

-   c) Het optionally substituted with (C₁₋₆)alkyl, —NH₂, —COOH, or    (C₂₋₄)alkenyl substituted with —COOH;

-   d) —SO₂N(R⁴³)R⁴⁴, wherein R⁴³ is H or (C₁₋₆)alkyl and R⁴⁴ is    selected from (C₁₋₆)alkyl, phenyl, phenyl-(C₁₋₄)alkyl-,    —C(═O)NH(C₁₋₄)alkyl, —C(═O)O(C₁₋₄)alkyl, and Het; wherein said    (C₁₋₆)alkyl is optionally substituted with —OH or —COOH and wherein    said Het is optionally substituted with (C₁₋₆)alkyl;    -   or R⁴³ and R⁴⁴, together with the N to which they are attached,        are linked together to form a 5- or 6-membered heterocycle which        may be saturated or unsaturated and which may optionally contain        from one to three further heteroatoms each independently        selected from N, O and S; said heterocycle being optionally        substituted with (C₁₋₆)alkyl or —COOH;

-   e) —O—(C₁₋₄)alkyl substituted with —OH, —COOH or Het, wherein said    Het is optionally substituted with —COOH or —COO(C₁₋₆)alkyl;    -   provided that the carbon atom of —O—(C₁₋₄)alkyl which is        directly bonded to 0 is not also directly bonded to —OH;

-   f) —C(═O)N(R⁵)R⁶ or —O—CH₂—C(═O)N(R⁵)R⁶ wherein R⁵ is H or    (C₁₋₆)alkyl and R⁶ is selected from:    -   i) phenyl optionally substituted with one or two substituents        each independently selected from —OH, —COOH, —N((C₁₋₄)alkyl)₂,        (C₁₋₄)alkyl, (C₂₋₄)alkenyl and Het; wherein said (C₁₋₄)alkyl is        optionally substituted with —COOH and said (C₂₋₄)alkenyl is        substituted with —COOH;    -   ii) (C₁₋₄)alkyl optionally substituted with one or two        substituents each independently selected from —COOH, —OH,        —S—(C₁₋₆)alkyl and Het;    -   provided that the carbon atom of (C₁₋₄)alkyl which is directly        bonded to N is not also directly bonded to —OH;    -   iii) phenyl-(C₁₋₄)alkyl- wherein the phenyl portion of said        phenyl-(C₁₋₄)alkyl- is optionally substituted with one or two        substituents each independently selected from —OH, —NH₂, and        —COOH;    -   iv) (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl- wherein the cycloalkyl portion        of said (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl- is optionally substituted        with —COOH;    -   v) Het optionally substituted with one or two substituents each        independently selected from (C₁₋₆)alkyl, phenyl-(C₁₋₄)alkyl- and        —COOH;    -   vi) (C₃₋₇)cycloalkyl; and    -   vii) —SO₂—R⁶¹ wherein R⁶¹ is (C₁₋₄)alkyl or phenyl;    -   or R⁵ and R⁶, together with the N to which they are attached,        are linked together to form a 5- or 6-membered heterocycle which        may be saturated or unsaturated and which may optionally contain        from one to three further heteroatoms each independently        selected from N, O and S; said heterocycle being optionally        substituted with one or two substituents each independently        selected from (C₁₋₆)alkyl, —COOH and —COO(C₁₋₆)alkyl;

-   g) —NHC(═O)—R⁷ wherein R⁷ is selected from:    -   i) (C₁₋₆)alkyl optionally substituted with one or two        substituents each independently selected from —COOH,        —O—(C₁₋₄)alkyl, —NHC(═O)—(C₁₋₄)alkyl, phenyl and Het; wherein        said phenyl is optionally substituted with one or two        substituents each independently selected from halo, —OH,        —O—(C₁₋₄)alkyl, —NO₂, —COOH, —NH₂, —NH(C₁₋₄)alkyl,        —N((C₁₋₄)alkyl)₂, and (C₁₋₆)alkyl optionally substituted with        from one to three halo substituents;    -   ii) phenyl optionally substituted with —OH, halo or —COOH;    -   iii) —NHR⁷¹ wherein R⁷¹ is phenyl or phenyl-(C₁₋₄)alkyl-,        wherein said phenyl is optionally substituted with —COOH or        —COO(C₁₋₄)alkyl; and    -   iv) (C₁₋₆)alkynyl, (C₃₋₇)cycloalkyl or        (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-;

-   h) —NHSO₂R⁸ wherein R⁸ is selected from phenyl, phenyl-(C₁₋₄)alkyl-    and Het; and

-   i) —C≡C—R⁹ wherein R⁹ is selected from:    -   i) H, —COOH, —COO(C₁₋₆)alkyl, phenyl or (C₂₋₄)alkenyl;    -   ii) (C₃₋₇)cycloalkyl optionally substituted with —OH, —COOH,        —COO(C₁₋₆)alkyl, or (C₁₋₄)alkyl wherein said (C₁₋₄)alkyl is        optionally substituted with —OH or —N(R⁹¹)R⁹², wherein R⁹¹ is H        and R⁹² is (C₁₋₄)alkyl substituted with Het; or R⁹¹ and R⁹²,        together with the N to which they are attached, are linked        together to form a 5- or 6-membered heterocycle which may be        saturated, unsaturated or aromatic and which may optionally        contain from one to three further heteroatoms each independently        selected from N, O and S; said heterocycle being optionally        substituted with one or two substituents each independently        selected from (C₁₋₆)alkyl and —OH; and    -   iii) (C₁-)alkyl optionally substituted with one, two or three        substituents each independently selected from:        -   a) —OH, —O(C═O)NH₂, —O(C═O)NH(C₁₋₄)alkyl, CF₃, —COOH or            —COO—(C₁₋₄)alkyl;        -   b) Het optionally substituted with (C₁₋₆)alkyl or —OH;        -   c) —N(R⁹³)R⁹⁴ wherein R⁹³ is H or (C₁₋₄)alkyl and R⁹⁴ is            selected from H, —(C₁₋₄)alkyl optionally substituted with            R⁹⁴¹, —SO₂-(C₁₋₄)alkyl and —C(═O)—R⁹⁴²;            -   wherein R⁹⁴¹ is —COOH, —C(═O)NH₂, (C₃₋₇)cycloalkyl, Het,                or phenyl optionally substituted with —OH,            -   and R⁹⁴² is —O—(C₁₋₄)alkyl, —NH—(C₁₋₄)alkyl, phenyl,                (C₃₋₇)cycloalkyl or Het, wherein said (C₃₋₇)cycloalkyl                is optionally substituted with —COOH and wherein said                Het is optionally substituted with one or two                substituents each independently selected from                (C₁₋₆)alkyl and —OH; or R⁹⁴² is (C₁₋₄)alkyl optionally                substituted with —COOH, —NH₂, —NH(C₁₋₄)alkyl, —NH-Het,                —N((C₁₋₄)alkyl)₂, or Het; wherein said Het is optionally                substituted with one or two substituents each                independently selected from —OH, —COOH and (C₁₋₆)alkyl                optionally substituted with Het and wherein the                (C₁₋₄)alkyl portion of said —NH(C₁₋₄)alkyl is optionally                substituted with Het;        -   d) —C(═O)N(R⁹⁵)R⁹⁶, wherein R⁹⁵ is H and R⁹⁶ is selected            from (C₃₋₇)cycloalkyl, —SO₂—R⁹⁶¹ and —(C₁₋₄)alkyl-R⁹⁶²,            wherein            -   R⁹⁶¹ is (C₁₋₄)alkyl, phenyl, (C₃₋₇)cycloalkyl, or                —N((C₁₋₄)alkyl)₂; and            -   R⁹⁶² is phenyl, —COOH, —N((C₁₋₄)alkyl)₂, or Het, wherein                said phenyl is optionally substituted with                —N((C₁₋₄)alkyl)₂ and said Het is optionally substituted                with oxo;            -   or R⁹⁵ and R⁹⁶, together with the N to which they are                attached, are linked together to form a 5- or 6-membered                heterocycle which may be saturated or unsaturated and                which may optionally contain from one to three further                heteroatoms each independently selected from N, O and S;                said heterocycle being optionally substituted with                —COOH; and        -   e) —O(C₁₋₄)alkyl optionally substituted with R⁹⁷ wherein R⁹⁷            is selected from —OH, —COOH, —C(═O)O—(C₁₋₄)alkyl-N            H(C₁₋₄)alkyl, —C(═O)N(R⁹⁷¹)R⁹⁷², —NH₂, —NH—(C₃₋₇)cycloalkyl,            —O-Het, and Het;            -   provided that the carbon atom of —O—(C₁₋₄)alkyl which is                directly bonded to O is not also directly bonded to —OH,                —NH₂ or —NH—(C₃₋₇)cycloalkyl;            -   wherein each of said Het and the Het portion of said                —O-Het is optionally substituted with one or two                substituents each independently selected from halo, oxo,                (C₁₋₄)alkyl, and —OH; and            -   wherein R⁹⁷¹ is H or (C₁₋₄)alkyl and R⁹⁷² is selected                from H, —OH, —NHC(═O)—(C₁₋₄)alkyl, —NHC(═O)—NH₂,                (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl, phenyl and Het, wherein                said (C₁₋₄)alkyl is optionally substituted with —OH,                —COOH, —N((C₁₋₄)alkyl)₂ or Het, provided that when R⁹⁷²                is (C₁₋₄)alkyl, the carbon atom of (C₁₋₄)alkyl which is                directly bonded to N is not also directly bonded to —OH;            -   and wherein said (C₃₋₇)cycloalkyl is optionally                substituted with —COOH, and wherein said phenyl is                optionally substituted with —OH, —COOH, or                —(C₂₋₄)alkenyl-COOH;            -   or R⁹⁷¹ and R⁹⁷², together with the N to which they are                attached, are linked together to form a 5- or 6-membered                heterocycle which may be saturated or unsaturated and                which may optionally contain from one to three further                heteroatoms each independently selected from N, O and S;                said heterocycle being optionally substituted with                (C₁₋₄)alkyl or —COOH;                wherein Het is a 4,5- or 6-membered heterocycle or a 9-                or 10-membered heterobicycle, each of which may be                saturated, unsaturated or aromatic and each of which                containing from one to four heteroatoms each                independently selected from N, O and S, wherein each                said N heteroatom may, independently and where possible,                exist in an oxidized state such that it is further                bonded to an O atom to form an N-oxide group and wherein                each said S heteroatom may, independently and where                possible, exist in an oxidized state such that it is                further bonded to one or two oxygen atoms to form the                groups SO or SO₂;                or an enantiomer, diastereoisomer or tautomer thereof,                including a salt or ester thereof.

According to a further aspect of the invention, there is provided apharmaceutical composition, comprising a compound of formula (I) asdefined hereinbefore and hereinafter, or a pharmaceutically acceptablesalt or ester thereof, and optionally one or more pharmaceuticallyacceptable carriers.

According to yet another aspect of the invention, there is provided apharmaceutical composition, comprising a compound of formula (I) asdefined hereinbefore and hereinafter, or a pharmaceutically acceptablesalt or ester thereof, in combination with one or more otherantiretroviral drugs.

According to another aspect of the invention, there is provided apharmaceutical composition for the treatment or prevention of HIVinfection, comprising a compound of formula (I) as defined hereinbeforeand hereinafter, or a pharmaceutically acceptable salt or ester thereof,and optionally one or more pharmaceutically acceptable carriers.

A further aspect of the invention provides a pharmaceutical compositionfor the treatment or prevention of HIV infection, comprising a compoundof formula (I) as defined hereinbefore and hereinafter, or apharmaceutically acceptable salt or ester thereof, and optionally one ormore pharmaceutically acceptable carriers, in combination with one ormore other antiretroviral drugs.

Another important aspect of the invention involves a method of treatingor preventing an HIV infection in a mammal by administering to themammal an anti-HIV effective amount of a compound of formula (I) asdefined hereinbefore and hereinafter, a pharmaceutically acceptable saltor ester thereof, or a composition as described above, alone or incombination with at least one other antiretroviral agent, administeredtogether or separately.

Still another aspect of the invention provides the use of a compound offormula (I) as defined hereinbefore and hereinafter, or apharmaceutically acceptable salt or ester thereof, for the treatment orprevention of HIV infection in a mammal.

According to another aspect of the invention, there is provided a methodof inhibiting HIV-1 replication by exposing the virus to an inhibitoryamount of a compound of formula (I) as defined hereinbefore andhereinafter, or a pharmaceutically acceptable salt or ester thereof.

Yet another aspect of the invention provides the use of a compound offormula (I) as defined hereinbefore and hereinafter, or apharmaceutically acceptable salt or ester thereof, to inhibit HIV-1replication.

According to another aspect of the invention, there is provided the useof a compound of formula (I) as defined hereinbefore and hereinafter, ora pharmaceutically acceptable salt or ester thereof, for the manufactureof a medicament for the treatment or prevention of an HIV infection.

According to yet another aspect of the invention, there is provided theuse of a compound of formula (I) as defined hereinbefore andhereinafter, or a pharmaceutically acceptable salt or ester thereof, forthe manufacture of a medicament for the treatment or prevention of anHIV infection, in combination with one or more other antiretroviraldrugs.

Another aspect of the invention provides an article of manufacturecomprising a composition effective to treat an HIV infection or toinhibit the reverse transcriptase of HIV; and packaging materialcomprising a label which indicates that the composition can be used totreat infection by the human immunodeficiency virus; wherein thecomposition comprises a compound of formula (I) as defined hereinbeforeand hereinafter, or a pharmaceutically acceptable salt or ester thereof.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The following definitions apply unless otherwise noted:

As used herein, the term “(C_(1-n))alkyl”, either alone or incombination with another radical, is intended to mean acyclic straightor branched chain alkyl radicals containing from one to n carbon atomsrespectively. Examples of such radicals include, but are not limited to,methyl (Me), ethyl (Et), propyl (Pr), 1-methylethyl (iPr), butyl (Bu),1-methylpropyl, 2-methylpropyl (iBu), and 1,1-dimethylethyl (tBu),wherein the abbreviations commonly used herein are given in brackets.

As used herein, the term “—O—(C_(1-n))alkyl”, either alone or incombination with another radical, refers to alkoxy radicals containingfor one to n carbon atoms and includes, but is not limited to, methoxy(—OMe), ethoxy (—OEt), propoxy (—OPr), 1-methylethoxy (-OiPr), butoxy(—OBu) and 1,1-dimethylethoxy (-OtBu), wherein the abbreviationscommonly used herein are given in brackets. When an —O—(C_(1-n))alkylgroup is substituted, it is understood to be substituted on the(C_(1-n))alkyl portion thereof.

As used herein, the term “—S—(C_(1-n))alkyl”, either alone or incombination with another radical, refers to alkylthio radicalscontaining one to n carbon atoms and includes methylthio (-SMe),ethylthio (-SEt), propylthio (-SPr), 1-methylethylthio (-S-iPr),butylthio (-SBu) and 1,1-dimethylethylthio (-StBu), wherein theabbreviations commonly used herein are given in brackets. When an—S—(C_(1-n))alkyl group is substituted, it is understood to besubstituted on the (C_(1-n))alkyl portion thereof.

The term “oxo” as used herein means an oxygen atom attached to a carbonatom as a substituent by a double bond (═O).

The term “thioxo” as used herein means an sulfur atom attached to acarbon atom as a substituent by a double bond (═S).

As used herein, the term “halo” means a halo radical selected frombromo, chloro, fluoro or iodo.

As used herein, the term “(C₂-n)alkenyl”, either alone or used withanother radical, means an unsaturated, acyclic radical containing two ton carbon atoms, at least two of which are bonded to each other by adouble bond and includes, but is not limited to, —CH═CH₂, —CH₂CH═CH₂,—CH₂CH═CHCH₃ and —CH(Me)CH═CH₂. The cis and trans isomers, and mixturesthereof, of the (C₂-n)alkenyl radical can be encompassed by the term. A(C₂-n)alkenyl radical may be substituted on any of the carbon atomsthereof which would otherwise bear a hydrogen atom.

The term “(C₂-n)alkynyl”, as used herein, wherein n is an integer,either alone or in combination with another radical, is intended to meanan unsaturated, acyclic straight chain radical containing two to ncarbon atoms, at least two of which are bonded to each other by a triplebond. Examples of such radicals include, but are not limited to,ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.

The term “(C₃-m)cycloalkyl” as used herein, wherein m is an integer,either alone or in combination with another substituent, means acycloalkyl substituent containing from 3 to m carbon atoms and includes,but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyland cycloheptyl.

The term “(C₃-m)cycloalkyl-(C_(1-n))alkyl-” as used herein, wherein nand m are both integers, means an alkyl radical containing from 1 to ncarbon atoms to which a cycloalkyl radical containing from 3 to m carbonatoms is directly linked; including, but not limited to,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,1-cyclopentylethyl, 2-cyclopentylethyl, cyclohexylmethyl,1-cyclohexylethyl and 2-cyclohexylethyl. When a(C₃-m)cycloalkyl-(C_(1-n))alkyl- group is substituted, it is understood,unless otherwise specified, that the substituent may be attached toeither the cycloalkyl or the alkyl portion thereof.

The term “phenyl-(C_(1-n))alkyl-” as used herein, wherein n is aninteger, means an alkyl radical containing from 1 to n carbon atoms towhich a phenyl radical is directly linked; including, but not limitedto, phenylmethyl (also known as benzyl), 1-phenylethyl, 2-phenylethyl,2-phenyl-1-methylethyl, 1-phenyl-1-methylethyl, 1-phenylpropyl,2-phenylpropyl, and 3-phenylpropyl. When a phenyl-(C_(1-n))alkyl-groupis substituted, it is understood, unless otherwise specified, that thesubstituent may be attached to either the phenyl or the alkyl portionthereof.

As used herein, the term “Het” is defined as a 4,5- or 6-memberedheterocycle or a 9- or 10-membered heterobicycle, each of which may besaturated, unsaturated or aromatic and each of which containing from oneto four heteroatoms each independently selected from N, O and S, whereineach said N heteroatom may, independently and where possible, exist inan oxidized state such that it is further bonded to an O atom to form anN-oxide group and wherein each said S heteroatom may, independently andwhere possible, exist in an oxidized state such that it is furtherbonded to one or two oxygen atoms to form the groups SO or SO₂, unlessotherwise specified.

As used herein, the term “heterocycle”, either alone or in combinationwith another radical, is intended to mean a monovalent radical derivedby removal of a hydrogen from a 5- or 6-membered saturated orunsaturated (including aromatic) heterocycle containing 1 to 4heteroatoms selected from N, O and S. Examples of such heterocyclesinclude, but are not limited to, azetidine, pyrrolidine,tetrahydrofuran, thiazolidine, pyrrole, furan, thiophene, 1H-imidazole,isoxazole, oxazole, thiazole, tetrazole, piperidine, piperazine,1,4-dioxane, 4-morpholine, 4-thiomorpholine, pyridine, pyridine-N-oxide,pyridazine, pyrazine or pyrimidine, or the following heterocycles:

As used herein, the term “heterobicycle” either alone or in combinationwith another radical, means a heterocycle as defined above fused toanother cycle, be it a heterocycle, a phenyl or any other cycle.Examples of such heterobicycles include, but are not limited to, indole,benzimidazole, benzofuran, thiazolo[4,5-b]-pyridine, quinoline,isoquinoline, or coumarin, or the following:

As used herein, the term “inhibitor of HIV replication” refers to anagent capable of substantially reducing or essentially eliminating theability of HIV-1 reverse transcriptase to replicate a DNA copy from anRNA template.

As used herein, the term “single or double mutant strains” means thateither one or two amino acid residues that are present in WT HIV-1strain have been replaced by residues not found in the WT strain. Forexample, for the single mutant Y181C, the tyrosine at residue 181 hasbeen replaced by a cysteine residue. Similarly, for the double mutantK103NNY181C, an asparagine residue has replaced the lysine at residue103 and a cysteine residue has replaced the tyrosine at residue 181.

The term “salt thereof” means any acid and/or base addition salt of acompound according to the invention; preferably a pharmaceuticallyacceptable salt thereof.

As used herein, the term “pharmaceutically acceptable salt” means a saltof a compound which is, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, generally water oroil-soluble or dispersible, and effective for their intended use. Whereapplicable and compatible with the chemical properties of the compoundof formula (I), the term includes pharmaceutically-acceptable acidaddition salts and pharmaceutically-acceptable base addition salts.Lists of suitable salts are found in, e.g., S. M. Birge et al., J.Pharm. Sci., 1977, 66, pp. 1-19.

The term “pharmaceutically-acceptable acid addition salt” means thosesalts which retain the biological effectiveness and properties of thefree bases and which are not biologically or otherwise undesirable,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoricacid, and the like, and organic acids such as acetic acid,trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,2-acetoxybenzoic acid, butyric acid, camphoric acid, camphorsulfonicacid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid,glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfic acid,heptanoic acid, hexanoic acid, formic acid, fumaric acid,2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, maleicacid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid,mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid,nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid,pectinic acid, phenylacetic acid, 3-phenylpropionic acid, picric acid,pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearicacid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonicacid, undecanoic acid, and the like.

The term “pharmaceutically-acceptable base addition salt” means thosesalts which retain the biological effectiveness and properties of thefree acids and which are not biologically or otherwise undesirable,formed with inorganic bases such as ammonia or hydroxide, carbonate, orbicarbonate of ammonium or a metal cation such as sodium, potassium,lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum,and the like. Particularly preferred are the ammonium, potassium,sodium, calcium, and magnesium salts. Salts derived frompharmaceutically-acceptable organic nontoxic bases include salts ofprimary, secondary, and tertiary amines, quaternary amine compounds,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion-exchange resins, such as methylamine,dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine,isopropylamine, tripropylamine, tributylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine,choline, betaine, ethylenediamine, glucosamine, methylglucamine,theobromine, purines, piperazine, piperidine, N-ethylpiperidine,tetramethylammonium compounds, tetraethylammonium compounds, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, N,N′-dibenzylethylenediamine, polyamine resins, and thelike. Particularly preferred organic nontoxic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline,and caffeine.

The term “ester thereof” means any ester of a compound in which any ofthe carboxyl functions of the molecule is replaced by an alkoxycarbonylfunction, including but not limited to pharmaceutically acceptableesters thereof.

The term “pharmaceutically acceptable ester” as used herein, eitheralone or in combination with another substituent, means esters of thecompound of formula (I) in which any of the carboxyl functions of themolecule, but preferably the carboxy terminus, is replaced by analkoxycarbonyl function:

in which the R moiety of the ester is selected from alkyl (e.g. methyl,ethyl, n-propyl, tert-butyl, n-butyl); alkoxyalkyl (e.g. methoxymethyl);alkoxyacyl (e.g. acetoxymethyl); aralkyl (e.g. benzyl); aryloxyalkyl(e.g. phenoxymethyl); aryl (e.g. phenyl), optionally substituted withhalogen, (C₁₋₄)alkyl or (C₁₋₄)alkoxy. Other suitable esters can be foundin Design of prodrugs, Bundgaard, H. Ed. Elsevier (1985). Suchpharmaceutically acceptable esters are usually hydrolyzed in vivo whenadministered to a mammal and transformed into the acid form of thecompound of formula (I). With regard to the esters described above,unless otherwise specified, any alkyl moiety present advantageouslycontains 1 to 16 carbon atoms, particularly 1 to 6 carbon atoms. Anyaryl moiety present in such esters advantageously comprises a phenylgroup. In particular the esters may be a (C₁₋₁₆)alkyl ester, anunsubstituted benzyl ester or a benzyl ester substituted with at leastone halogen, (C₁₋₆)alkyl, (C₁₋₆)alkoxy, nitro or trifluoromethyl.

As used herein, the designation whereby a bond is drawn as emanatingfrom the center of a ring, such as, for example,

means that the bond may be attached to any free position on the ringthat would otherwise be substituted by a hydrogen atom, unless specifiedotherwise. Such bonds may be linked to substituents of the ring or mayindicate the linkage of the ring as a substituent on another structure.

As used herein, the term “treatment” means the administration of acompound or composition according to the present invention to alleviateor eliminate symptoms of the HIV disease and/or to reduce viral load ina patient.

As used herein, the terms “prevention” and “prophylaxis”, usedinterchangeably, mean the administration of a compound or compositionaccording to the present invention post-exposure of the individual tothe virus but before the appearance of symptoms of the disease, and/orprior to the detection of the virus in the blood, to prevent theappearance of symptoms of the disease and/or to prevent the virus fromreaching detectible levels in the blood and the administration of acompound or composition according to the present invention to preventperinatal transmission of HIV-1 from mother to baby, by administrationto the mother before giving birth and to the child within the first daysof life.

The following signs

are used in sub-formulas to indicate the bond which is connected to therest of the molecule as defined.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In the following preferred embodiments, groups and substituents of thecompounds of formula (I) according to this invention are described indetail.

Ar:

According to a preferred embodiment of the first aspect of the presentinvention there is provided a compound of formula (I)

wherein X, R¹, R², R³ and R⁴ are as defined herein and wherein Ar isselected from:

wherein R^(Ar) is as defined herein and wherein the designation

represents the bond to R¹ and the designation

represents the bond to X.

More preferably, Ar is selected from

Most preferably, Ar is

Therefore, the present invention preferably provides compounds offormulas (Ia) to (Ii):

wherein X, R^(Ar), R¹, R², R³ and R⁴ are as defined herein.

More preferably, the present invention provides compounds of formulas:

wherein X, R^(Ar), R¹, R², R³ and R⁴ are as defined herein.

R^(Ar) is preferably selected from H. CH₃, CF₃ and cyclopropyl.

Most preferably, the present invention provides compounds of formula(Ia)

wherein X, R¹, R², R³ and R⁴ are as defined herein.

Any and each individual definition of Ar as set out herein may becombined with any and each individual definition of X, R¹, R², R³ and R⁴as set out herein.

X:

When Ar, R¹, R², R³ and R⁴ are as defined hereinbefore and hereinafter,preferably, X is S.

Any and each individual definition of X as set out herein may becombined with any and each individual definition of Ar, R¹, R², R³ andR⁴ as set out herein.

R¹:

When Ar, X, R², R³ and R⁴ are as defined hereinbefore and hereinafter,R¹ is a group of formula:

R¹¹ is preferably chloro or bromo.

More preferably, R¹¹ is chloro.

Preferably, R¹² is selected from H, (C₁₋₄)alkyl, CF₃, (C₃₋₇)cycloalkyland halo or R¹² and R¹³ are linked, together with the carbon atoms towhich they are attached, to form a five- or six-membered saturated,unsaturated or aromatic ring which optionally contains from one to threeheteroatoms each independently selected from O, S and N.

More preferably, R¹² is selected from H, methyl, CF₃, chloro, bromo andcyclopropyl; or R¹² and R¹³ are linked, together with the carbon atomsto which they are attached, so that R¹ is a fused ring system selectedfrom naphthyl, benzothiazolyl and quinolyl.

Still more preferably, R¹² is H, CF₃ or cyclopropyl.

Most preferably, R¹² is H.

Preferably, R¹³ is selected from H, (C₁₋₄)alkyl, CF₃, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-, —O—(C₁₋₄)alkyl, —N((C₁₋₄)alkyl)₂ and—OCF₃; wherein the (C₃₋₇)cycloalkyl is optionally substituted with(C₁₋₄)alkyl; or R¹² and R¹³ or R¹³ and R¹⁴ are linked, together with thecarbon atoms to which they are attached, to form a five- or six-memberedsaturated, unsaturated or aromatic ring which optionally contains fromone to three heteroatoms each independently selected from O, S and N.

More preferably, R¹³ is selected from H, methyl, CF₃, 1-methylethyl,1,1-dimethylethyl, cyclopropyl, cyclopropylmethyl, 1-methylcyclopropyl,and —OCF₃; or R¹² and R¹³ or R¹³ and R¹⁴ are linked, together with thecarbon atoms to which they are attached, so that R¹ is a fused ringsystem selected from naphthyl, benzothiazolyl, indanyl and quinolyl.

Most preferably, R¹³ is H, methyl, 1,1-dimethylethyl or cyclopropyl.

Preferably, R¹⁴ is selected from H, halo, cyano, (C₁₋₄)alkyl, CF₃,(C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-, —O—(C₁₋₄)alkyl, and—N((C₁₋₄)alkyl)₂ or R¹³ and R¹⁴ are linked, together with the carbonatoms to which they are attached, to form a five- or six-memberedsaturated, unsaturated or aromatic ring which optionally contains fromone to three heteroatoms each independently selected from O, S and N.

More preferably, R¹⁴ is selected from H, fluoro, chloro, bromo, cyano,methyl, CF₃, 1,1-dimethylethyl, cyclopropyl, cyclopropylmethyl, methoxy,1-methylethoxy, and dimethylamino, or R¹³ and R¹⁴ are linked, togetherwith the carbon atoms to which they are attached, so that R¹ is a fusedring system selected from naphthyl and indanyl.

Still more preferably, R¹⁴ is H, cyclopropyl or CF₃.

Most preferably, R¹⁴ is H.

Preferably, R¹⁵ is selected from H, halo, (C₁₋₄)alkyl and CF₃.

More preferably, R¹⁵ is H, fluoro, chloro, methyl or CF₃.

Most preferably, R¹⁵ is H.

Therefore, preferred R¹ substituents are selected from:

More preferably, R¹ is selected from:

Most preferably, R¹ is selected from:

Any and each individual definition of R¹ as set out herein may becombined with any and each individual definition of Ar, X, R², R³ and R⁴as set out herein.

R²:

When Ar, X, R¹, R³ and R⁴ are as defined hereinbefore and hereinafter,preferably, R² is selected from halo, nitro and methyl.

More preferably, R² is halo or nitro.

Even more preferably, R² is halo.

Yet more preferably, R² is chloro or bromo.

Most preferably, R² is chloro.

Any and each individual definition of R² as set out herein may becombined with any and each individual definition of Ar, X, R¹, R³ and R⁴as set out herein.

-   R³.

When Ar, X, R¹, R² and R⁴ are as defined hereinbefore and hereinafter,most preferably, R³ is H or fluoro.

Any and each individual definition of R³ as set out herein may becombined with any and each individual definition of Ar, X, R¹, R² and R⁴as set out herein.

-   R⁴

When Ar, X, R¹, R² and R³ are as defined hereinbefore and hereinafter,R⁴ is preferably defined as follows.

In one alternative embodiment, R⁴ is

wherein R⁴² is bonded to position 2 or position 3 of the phenyl ring andis selected from H, halo and (C₁₋₄)alkyl; and R⁴¹ is bonded to position3 or position 4 of the phenyl ring and is selected from:

-   -   i) (C₁₋₄)alkyl substituted with —COOH, —COO(C₁₋₄)alkyl,        —C(═O)NH₂, —C(═O)NHSO₂-(C₁₋₄)alkyl, or —OH;    -   ii) (C₂₋₄)alkenyl substituted with —COOH or —COO(C₁₋₄)alkyl;    -   iii)-O—(C₁₋₄)alkyl optionally substituted with —COOH, Het, or        —N((C₁₋₆)alkyl)₂, wherein Het is a 5- or 6-membered saturated,        unsaturated or aromatic monocyclic heterocycle containing 1 to 4        heteroatoms each independently selected from O, S and N, wherein        each said S heteroatom may, independently and where possible,        exist in an oxidized state such that it is further bonded to one        or two oxygen atoms to form the groups SO or SO₂, said Het being        optionally substituted with —OH or —COOH; and wherein either or        both of the (C₁₋₆)alkyl groups in said —N((C₁₋₆)alkyl)₂ are        optionally substituted with —COOH or —COO(C₁₋₄)alkyl; and    -   iv) —OH, —COOH, —COO(C₁₋₄)alkyl, —SO₂NH₂, or —SO₂-(C₁₋₄)alkyl;    -   provided that R⁴² and R⁴¹ may not both be bonded to position 3        of the phenyl ring at the same time.

Preferably R⁴² is selected from H, Cl, F and CH₃. Most preferably, R⁴²is H.

Preferably R⁴¹ is selected from:

-   -   i) methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,        2-methylpropyl and 1,1-dimethylethyl, each of which being        substituted with —COOH, —COOCH₃, —COOCH₂CH₃—C(═O)NH₂,        —C(═O)NHSO₂—CH₃, or —OH;    -   ii) —CH═CH—COOH, —CH═CH—COOCH₃ or —CH═CH—COOCH₂CH₃;    -   iii) —O—CH₃ or —O—CH₂CH₃, each of which being optionally        substituted with —COOH, Het, or —N((C₁₋₄)alkyl)₂, wherein Het is        selected from

wherein said Het is optionally substituted with —OH or —COOH and whereineither or both of the (C₁₋₄)alkyl groups in said —N((C₁₋₄)alkyl)₂ areoptionally substituted with —COOH, —COOCH₃ or —COOCH₂CH₃; and

-   -   iv) —OH, —COOH, —COOCH₃, —COOCH₂CH₃, —SO₂NH₂, or —SO₂—CH₃.

More preferably within this embodiment, R⁴¹ is selected from —OH, —OCH₃,—COOH, —COOCH₃, —SO₂CH₃, —SO₂NH₂, —CH₂COOH, —CH₂COOCH₃, —CH₂CONH₂,—CH₂CH₂OH, —CH₂CH₂COOH, —CH₂CONHSO₂CH₃, —C(CH₃)₂—COOH, —OCH₂COOH,

Most preferably, R⁴¹ is selected from —CH₂COOH, —C(CH₃)₂—COOH,—OCH₂COOH,

In a preferable embodiment, R⁴¹ is bonded to position 4 of the phenylring.

In another alternative embodiment, R⁴ is selected from:

-   b) (C₂₋₄)alkenyl substituted with —COOH or —COO(C₁₋₄)alkyl;-   c) Het optionally substituted with (C₁₋₆)alkyl, —NH₂, —COOH, or    (C₂₋₄)alkenyl substituted with —COOH, wherein Het is a 5- or    6-membered aromatic monocyclic heterocycle containing 1 to 4    heteroatoms each independently selected from O, S and N;-   d) —SO₂N(R⁴³)R⁴⁴, wherein R⁴³ is H or (C₁₋₆)alkyl and R⁴⁴ is    selected from (C₁₋₆)alkyl, phenyl, phenyl-(C₁₋₄)alkyl-,    —C(═O)NH(C₁₋₄)alkyl, —C(═O)O(C₁₋₄)alkyl, and Het wherein Het is a 5-    or 6-membered saturated, unsaturated or aromatic monocyclic    heterocycle containing 1 to 4 heteroatoms each independently    selected from O, S and N; wherein said (C₁₋₆)alkyl is optionally    substituted with —OH or —COOH and wherein said Het is optionally    substituted with (C₁₋₆)alkyl;    -   or R⁴³ and R⁴⁴, together with the N to which they are attached,        are linked together to form a 5- or 6-membered heterocycle which        may be saturated or unsaturated and which may optionally contain        from one to three further heteroatoms each independently        selected from N, O and S; said heterocycle being optionally        substituted with (C₁-)alkyl or —COOH;-   e) —O—(C₁₋₄)alkyl substituted with —OH, —COOH or Het wherein Het is    a 5- or 6-membered saturated, unsaturated or aromatic monocyclic    heterocycle containing 1 to 4 heteroatoms each independently    selected from O, S and N, wherein said Het is optionally substituted    with —COOH or —COO(C₁₋₆)alkyl; provided that the carbon atom of    —O—(C₁₋₄)alkyl which is directly bonded to 0 is not also directly    bonded to —OH; and-   h) —NHSO₂R⁸ wherein R⁸ is selected from phenyl, phenyl-(C₁₋₄)alkyl-    and Het wherein Het is a 5- or 6-membered saturated, unsaturated or    aromatic monocyclic heterocycle containing 1 to 4 heteroatoms each    independently selected from O, S and N.

Preferably within the scope of this embodiment, R⁴ is selected from:

-   b) (C₂₋₄)alkenyl substituted with —COOH or —COOCH₃;-   c) Het optionally substituted with CH₃, —NH₂, —COOH, or —CH═CH—COOH;    wherein Het is selected from

-   d) —SO₂N(R⁴³)R⁴⁴, wherein R⁴³ is H or CH₃ and R⁴⁴ is selected from    (C₁₋₄)alkyl, phenyl, phenyl-(C₁₋₄)alkyl-, —C(═O)NHCH₃, —C(═O)OCH₃,    and Het; wherein Het is selected from

and wherein said (C₁₋₄)alkyl is optionally substituted with —OH or —COOHand wherein said Het is optionally substituted with CH₃;

-   -   or R⁴³ and R⁴⁴, together with the N to which they are attached,        are linked together to form a 6-membered heterocycle which may        be saturated or unsaturated and which may optionally contain one        or two further heteroatoms each independently selected from N        and O; said heterocycle being optionally substituted with CH₃ or        —COOH;

-   e) —O—(C₁₋₄)alkyl substituted with —OH, —COOH or Het, wherein Het is    selected from

and wherein said Het is optionally substituted with —COOH, —COOCH₃ or—COOCH₂CH₃;

-   -   provided that the carbon atom of —O—(C₁₋₄)alkyl which is        directly bonded to 0 is not also directly bonded to —OH; and

-   h) —NHSO₂R⁸ wherein R⁸ is selected from phenyl, phenylmethyl and

More preferably within the scope of this embodiment R⁴ is selected from:

—SO₂NHMe, —SO₂NHCH(Me)₂, —SO₂N(Me)₂, —SO₂NH(CH₂)₂OH, —SO₂NHCH₂COOH,

and —NHSO₂R³ wherein

R⁸ is selected from phenyl, phenylmethyl and

In still another alternative embodiment, R⁴ is —C(═O)N(R⁵)R⁶ or—O—CH₂—C(═O)N(R⁵)R⁶ wherein R⁵ is H or (C₁₋₆)alkyl and R⁶ is selectedfrom:

-   -   i) phenyl optionally substituted with one or two substituents        each independently selected from —OH, —COOH, —N((C₁₋₄)alkyl)₂,        (C₁₋₄)alkyl, (C₂₋₄)alkenyl and Het wherein Het is a 5- or        6-membered saturated, unsaturated or aromatic monocyclic        heterocycle containing 1 to 4 heteroatoms each independently        selected from O, S and N; wherein said (C₁₋₄)alkyl is optionally        substituted with —COOH and said (C₂₋₄)alkenyl is substituted        with —COOH;    -   ii) (C₁₋₄)alkyl optionally substituted with one or two        substituents each independently selected from —COOH, —OH,        —S—(C₁₋₆)alkyl and Het wherein Het is a 5- or 6-membered        saturated, unsaturated or aromatic monocyclic heterocycle        containing 1 to 4 heteroatoms each independently selected from        O, S and N wherein each said N heteroatom may, independently and        where possible, exist in an oxidized state such that it is        further bonded to an O atom to form an N-oxide group;        -   provided that the carbon atom of (C₁₋₄)alkyl which is            directly bonded to N is not also directly bonded to —OH;    -   iii) phenyl-(C₁₋₄)alkyl- wherein the phenyl portion of said        phenyl-(C₁₋₄)alkyl- is optionally substituted with one or two        substituents each independently selected from —OH, —NH₂ and        —COOH;    -   iv) (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl- wherein the cycloalkyl portion        of said (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl- is optionally substituted        with —COOH;    -   v) Het optionally substituted with one or two substituents each        independently selected from (C₁₋₆)alkyl, phenyl-(C₁₋₄)alkyl- and        —COOH wherein Het is a 5- or 6-membered heterocycle or a 9- or        10-membered heterobicycle, each of which may be saturated,        unsaturated or aromatic and each of which may optionally contain        from one to four heteroatoms each independently selected from N,        O and S;    -   vi) (C₃₋₇)cycloalkyl; and    -   vii) —SO₂—R⁶ wherein R⁶¹ is (C₁₋₄)alkyl or phenyl;    -   or R⁵ and R⁶, together with the N to which they are attached,        are linked together to form a 5- or 6-membered heterocycle which        may be saturated or unsaturated and which may optionally contain        from one to three further heteroatoms each independently        selected from N, O and S; said heterocycle being optionally        substituted with one or two substituents each independently        selected from (C₁₋₆)alkyl, —COOH and —COO(C₁₋₆)alkyl.

More preferably within this embodiment, R⁴ is —C(═O)N(R⁵)R⁶ wherein R⁵and R⁶ are as defined herein.

Preferably, R⁵ is H or CH₃ and R⁶ is selected from

-   -   i) phenyl optionally substituted with one or two substituents        each independently selected from —OH, —COOH, —N(CH₃)₂, CH₃, COOH        —CH₂COOH, —CH₂CH₂COOH,

-   -   ii) (C₁₋₄)alkyl optionally substituted with one or two        substituents each independently selected from —COOH, —OH, —S—CH₃        and Het, wherein Het is selected from

provided that the carbon atom of (C₁₋₄)alkyl which is directly bonded toN is not also directly bonded to —OH;

-   -   iii) phenyl-CH₂— or phenyl-CH₂CH₂—, wherein the phenyl portion        of said phenyl-CH₂— or phenyl-CH₂CH₂— is optionally substituted        with one or two substituents each independently selected from        —OH, —NH₂, and —COOH;    -   iv) (4-carboxycyclohexyl)methyl;    -   v) Het optionally substituted with one or two substituents each        independently selected from methyl, phenylmethyl- and —COOH,        wherein said Het is selected from

-   -   vi) cyclopropyl;    -   vii) —SO₂—CH₃ and —SO₂-Ph;        or R⁵ and R⁶, together with the N to which they are attached,        are linked together to form a 6-membered saturated heterocycle        which may optionally contain one further heteroatom        independently selected from N and O; said heterocycle being        optionally substituted with one or two substituents each        independently selected from CH₃ and —COOH.

More preferably, the group —N(R⁵)R⁶ is selected from —NHCH₃, —NHCH₂CH₃,

Most preferably, the group —N(R⁵)R⁶ is selected from

In a further alternative embodiment, R⁴ is —NHC(═O)—R⁷ wherein R⁷ isselected from:

-   -   i) (C₁₋₆)alkyl optionally substituted with one or two        substituents each independently selected from —COOH,        —O—(C₁₋₄)alkyl, —NHC(═O)—(C₁₋₄)alkyl, phenyl and Het wherein Het        is a 5- or 6-membered heterocycle or a 9- or 10-membered        heterobicycle, each of which may be saturated, unsaturated or        aromatic and each of which may optionally contain from one to        four heteroatoms each independently selected from N, O and S        wherein each said N heteroatom may, independently and where        possible, exist in an oxidized state such that it is further        bonded to an O atom to form an N-oxide group; and wherein said        phenyl is optionally substituted with one or two substituents        each independently selected from halo, —OH, —O—(C₁₋₄)alkyl,        —NO₂, —COOH, —NH₂, —NH(C₁₋₄)alkyl, —N((C₁₋₄)alkyl)₂, and        (C₁₋₆)alkyl optionally substituted with from one to three halo        substituents;    -   ii) phenyl optionally substituted with —OH, halo or —COOH;    -   iii) —NHR⁷¹ wherein R⁷¹ is phenyl or phenyl-(C₁₋₄)alkyl-,        wherein said phenyl is optionally substituted with —COOH or        —COO(C₁₋₄)alkyl; and    -   iv) (C₁₋₆)alkynyl, (C₃₋₇)cycloalkyl or        (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-.

Preferably, R⁷ is selected from:

-   -   i) methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,        2-methylpropyl, 1,1-dimethylethyl, 1-methylbutyl, 2-methylbutyl        or 3-methylbutyl, each of which being optionally substituted        with one or two substituents each independently selected from        —COOH, —O—CH₃, —NHC(═O)—CH₃, phenyl and Het; wherein Het is        selected from

and wherein said phenyl is optionally substituted with one or twosubstituents each independently selected from halo, —OH, —O—CH₃, —NO₂,—COOH, —NH₂, —NHCH₃, —N(CH₃)₂, and CF₃;

-   -   ii) phenyl optionally substituted with —OH, Cl or —COOH;    -   iii) —NH-phenyl or phenyl-CH₂—NH—, wherein the phenyl portion of        said —NH-phenyl and phenyl-CH₂—NH— is optionally substituted        with —COOH, —COOCH₃ or —COOCH₂CH₃; and    -   iv) ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,        3-butynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl        cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or        cyclohexylmethyl.

More preferably, R⁷ is selected from:

Most preferably, R⁷ is selected from:

In yet another alternative embodiment, R⁴ is —C≡C—R⁹ wherein R⁹ isselected from:

-   -   i) H, —COOH, —COO(C₁₋₆)alkyl, phenyl or (C₂₋₄)alkenyl;    -   ii) (C₃₋₇)cycloalkyl optionally substituted with —OH, —COOH,        —COO(C₁₋₆)alkyl, or (C₁₋₄)alkyl wherein said (C₁₋₄)alkyl is        optionally substituted with —OH or —N(R⁹¹)R⁹², wherein R⁹¹ is H        and R⁹² is (C₁₋₄)alkyl substituted with Het; or R⁹¹ and R⁹²,        together with the N to which they are attached, are linked        together to form a 5- or 6-membered heterocycle which may be        saturated, unsaturated or aromatic and which may optionally        contain from one to three further heteroatoms each independently        selected from N, O and S; said heterocycle being optionally        substituted with one or two substituents each independently        selected from (C₁₋₆)alkyl and —OH; and    -   iii) (C₁₋₆)alkyl optionally substituted with one, two or three        substituents each independently selected from:        -   a) —OH, —O(C═O)NH₂, —O(C═O)NH(C₁₋₄)alkyl, CF₃, —COOH or            —COO—(C₁₋₄)alkyl;        -   b) Het optionally substituted with (C₁₋₆)alkyl or —OH;        -   c) —N(R⁹³)R⁹⁴ wherein R⁹³ is H or (C₁₋₄)alkyl and R⁹⁴ is            selected from H, —(C₁₋₄)alkyl optionally substituted with            R⁹⁴′, —SO₂—(C₁₋₄)alkyl and —C(═O)—R⁹⁴²;            -   wherein R⁹⁴¹ is —COOH, —C(═O)NH₂, (C₃₋₇)cycloalkyl, Het,                or phenyl optionally substituted with —OH,            -   and R⁹⁴² is —O—(C₁₋₄)alkyl, —NH—(C₁₋₄)alkyl, phenyl,                (C₃₋₇)cycloalkyl or Het, wherein said (C₃₋₇)cycloalkyl                is optionally substituted with —COOH and wherein said                Het is optionally substituted with one or two                substituents each independently selected from                (C₁₋₆)alkyl and —OH; or            -   R⁹⁴² is (C₁₋₄)alkyl optionally substituted with —COOH,                —NH₂, —NH(C₁₋₄)alkyl, —NH-Het, —N((C₁₋₄)alkyl)₂, or Het;                wherein said Het is optionally substituted with one or                two substituents each independently selected from —OH,                —COOH and (C₁-)alkyl optionally substituted with Het and                wherein the (C₁₋₄)alkyl portion of said —NH(C₁₋₄)alkyl                is optionally substituted with Het;        -   d) —C(═O)N(R⁹⁵)R⁹⁶, wherein R⁹⁵ is H and R⁹⁶ is selected            from (C₃₋₇)cycloalkyl, —SO₂—R⁹⁶¹ and —(C₁₋₄)alkyl-R⁹⁶²,            wherein            -   R⁹⁶¹ is (C₁₋₄)alkyl, phenyl, (C₃₋₇)cycloalkyl, or                —N((C₁₋₄)alkyl)₂; and            -   R⁹⁶² is phenyl, —COOH, —N((C₁₋₄)alkyl)₂, or Het, wherein                said phenyl is optionally substituted with                —N((C₁₋₄)alkyl)₂ and said Het is optionally substituted                with oxo;            -   or R⁹⁵ and R⁹⁶, together with the N to which they are                attached, are linked together to form a 5- or 6-membered                heterocycle which may be saturated or unsaturated and                which may optionally contain from one to three further                heteroatoms each independently selected from N, O and S;                said heterocycle being optionally substituted with                —COOH; and        -   e) —O(C₁₋₄)alkyl optionally substituted with R⁹⁷ wherein R⁹⁷            is selected from —OH, —COOH,            —C(═O)O—(C₁₋₄)alkyl-NH(C₁₋₄)alkyl, —C(═O)N(R⁹⁷¹)R⁹⁷², —NH₂,            —NH—(C₃₋₇)cycloalkyl, —O-Het, and Het;            -   provided that the carbon atom of —O—(C₁₋₄)alkyl which is                directly bonded to O is not also directly bonded to —OH,                —NH₂ or —NH—(C₃₋₇)cycloalkyl;            -   wherein each of said Het and the Het portion of said                —O-Het is optionally substituted with one or two                substituents each independently selected from halo, oxo,                (C₁₋₄)alkyl, and —OH; and            -   wherein R⁹⁷¹ is H or (C₁₋₄)alkyl and R⁹⁷² is selected                from H, —OH, —NHC(═O)—(C₁₋₄)alkyl, —NHC(═O)—NH₂,                (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl, phenyl and Het, wherein                said (C₁₋₄)alkyl is optionally substituted with —OH,                —COOH, —N((C₁₋₄)alkyl)₂ or Het, provided that when R⁹⁷²                is (C₁₋₄)alkyl, the carbon atom of (C₁₋₄)alkyl which is                directly bonded to N is not also directly bonded to —OH;            -   and wherein said (C₃₋₇)cycloalkyl is optionally                substituted with —COOH, and wherein said phenyl is                optionally substituted with —OH, —COOH, or                —(C₂₋₄)alkenyl-COOH;            -   or R⁹⁷¹ and R⁹⁷², together with the N to which they are                attached, are linked together to form a 5- or 6-membered                heterocycle which may be saturated or unsaturated and                which may optionally contain from one to three further                heteroatoms each independently selected from N, O and S;                said heterocycle being optionally substituted with                (C₁₋₄)alkyl or —COOH;                wherein Het is in each instance independently a 4,5- or                6-membered saturated, unsaturated or aromatic monocyclic                heterocycle containing from one to four heteroatoms each                independently selected from N, O and S, wherein each                said N heteroatom may, independently and where possible,                exist in an oxidized state such that it is further                bonded to an O atom to form an N-oxide group and wherein                each said S heteroatom may, independently and where                possible, exist in an oxidized state such that it is                further bonded to one or two oxygen atoms to form the                groups SO or SO₂.

Preferably, R⁹ is selected from:

-   -   i) H, —COOH, phenyl, ethenyl or 2-propenyl;    -   ii) cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of        which being optionally substituted with —OH, —COOH or CH₃,        wherein said CH₃ is optionally substituted with —OH or        —N(R⁹¹)R⁹², wherein R⁹¹ is H and R⁹² is

or R⁹¹ and R⁹², together with the N to which they are attached, arelinked together to form a 5- or 6-membered heterocycle which may besaturated, unsaturated or aromatic and which may optionally contain oneor two further heteroatoms each independently selected from N and O;said heterocycle being optionally substituted with one or twosubstituents each independently selected from CH₃ and —OH;

-   -   iii) methyl, ethyl, propyl, 1-methylethyl, butyl,        1-methylpropyl, 2methylpropyl, 1,1-dimethylethyl, pentyl or        1-ethylpropyl, each of which being optionally substituted with        one, two or three substituents each independently selected from:        -   a) —OH, —O(C═O)NH₂, —O(C═O)NHCH₃, CF₃, —COOH, —COOCH₃ or            —COOCH₂CH₃;        -   b) Het optionally substituted with CH₃ or —OH; wherein Het            is selected from

-   -   -   c) —N(R⁹³)R⁹⁴ wherein R⁹³ is H, CH₃ or CH₂CH₃ and R⁹⁴ is            selected from H, —(C₁₋₄)alkyl optionally substituted with            R⁹⁴¹, —SO₂—CH₃ and —C(═O)—R⁹⁴²;            -   wherein R⁹⁴¹ is —COOH, —C(═O)NH₂, cyclopropyl, Het, or                phenyl optionally substituted with —OH; wherein Het is                selected from

-   -   -   -   and R⁹⁴² is —O—(C₁₋₄)alkyl, —NH—(C₁₋₄)alkyl, phenyl,                cyclopropyl or Het; wherein Het is selected from

and wherein said cyclopropyl is optionally substituted with —COOH andwherein said Het is optionally substituted with CH₃ or —OH; or

-   -   -   -   R⁹⁴² is (C₁₋₄)alkyl optionally substituted with —COOH,                —NH₂, —NH(C₁₋₄)alkyl,

—N((C₁₋₄)alkyl)₂, or

-   -   -   -   Het; wherein Het is selected from

and wherein said Het is optionally substituted with one or twosubstituents each independently selected from —OH, —COOH and (C₁₋₄)alkyloptionally substituted with

and wherein the (C₁₋₄)alkyl portion of said —NH(C₁₋₄)alkyl is optionallysubstituted with

-   -   -   d) —C(═O)N(R⁹⁵)R⁹⁶, wherein R⁹⁵ is H and R⁹⁶ is selected            from cyclopropyl, —SO₂—R⁹⁶¹ and —(C₁₋₄)alkyl-R⁹⁶², wherein            -   R⁹⁶¹ is CH₃, CH₂CH₃, phenyl, cyclopropyl, or —N(CH₃)₂;                and            -   R⁹⁶² is phenyl, —COOH, —N(CH₃)₂, or Het; wherein Het is                selected from

and wherein said phenyl is optionally substituted with —N(CH₃)₂ and saidHet is optionally substituted with oxo;

-   -   -   -   or R⁹⁵ and R⁹⁶, together with the N to which they are                attached, are linked together to form a 6-membered                heterocycle which may be saturated or unsaturated and                which may optionally contain one or two further                heteroatoms each independently selected from N and O;                said heterocycle being optionally substituted with                —COOH; and

        -   e) —O(C₁₋₄)alkyl optionally substituted with R⁹⁷ wherein R⁹⁷            is selected from —OH, —COOH, —C(═O)O—CH₂CH₂—NHCH₃,            —C(═O)N(R⁹⁷¹)R⁹⁷², —NH₂, —NH—(C₃₋₇)cycloalkyl,

and Het; provided that the carbon atom of —O—(C₁₋₄)alkyl which isdirectly bonded to O is not also directly bonded to —OH, —NH₂ or—NH—(C₃₋₇)cycloalkyl;wherein Het is selected from

and N and wherein said Het is optionally substituted with one or twosubstituents each independently selected from halo, oxo, CH₃ and —OH;and

-   -   -   -   wherein R⁹⁷¹ is H or CH₃ and R⁹⁷² is selected from H,                —OH, —NHC(═O)—CH₃, —NHC(═O)—NH₂, (C₁₋₄)alkyl,                cyclopropyl, phenyl and Het; wherein Het is selected                from

and wherein said (C₁₋₄)alkyl is optionally substituted with —OH, —COOH,—N(CH₃)₂ or

provided that when R⁹⁷² is (C₁₋₄)alkyl, the carbon atom of (C₀₋₄)alkylwhich is directly bonded to N is not also directly bonded to —OH;

-   -   -   -   and wherein said cyclopropyl is optionally substituted                with —COOH, and wherein said phenyl is optionally                substituted with —OH, —COOH, or —CH═CH—COOH;            -   or R⁹⁷¹ and R⁹⁷², together with the N to which they are                attached, are linked together to form a 5- or 6-membered                heterocycle which may be saturated or unsaturated and                which may optionally contain one or two further                heteroatoms each independently selected from N and O;                said heterocycle being optionally substituted with CH₃                or —COOH.

More preferably, R⁹ is selected from H, —COOH,

—(CH₂)₂CH₃, —CH₂OH, —(CH₂)₂OH, —(CH₂)₃OH, —(CH₂)₄OH, —C(Me)₂OH,—C(Me)₂CH₂OH,

—C(Me)₂Ome,

—CH₂N(Et)₂, —CH₂COOH, —(CH₂)₂COOH, —C(Me)₂CO₂H, —C(Me)₂COOMe,—C(Me)₂CH₂COOH, —CH₂OC(O)NH₂, —(CH₂)₃OC(O)NH₂,

Still more preferably, R⁹ is selected from —COOH,

—(CH₂)₂CH₃, —CH₂OH, —(CH₂)₂OH, —(CH₂)₃OH, —C(Me)₂OH, —C(Me)₂CH₂OH,—C(Me)₂OMe,

—CH₂COOH, —(CH₂)₂COOH, —C(Me)₂CO₂H, —C(Me)₂COOMe, —C(Me)₂CH₂COOH,—CH₂OC(O)NH₂, —(CH₂)₃OC(O)NH₂,

Most preferably, R⁹ is selected from

—CH₂OH, —(CH₂)₂OH, —(CH₂)₃OH, —C(Me)₂OH, —C(Me)₂CH₂₂H,

—C(Me)₂CO₂H,

Any and each individual definition of R⁴ as set out herein may becombined with any and each individual definition of Ar, X, R¹, R² and R³as set out herein.

Therefore, one embodiment of this invention provides a compound,represented by formula (I):

wherein

-   Ar is a 5-membered aromatic heterocycle containing 1 to 4    heteroatoms each independently selected from N, O and S; said    heterocycle being optionally substituted at a substitutable position    with R^(Ar), wherein R^(Ar) is H, (C₁₋₄)alkyl, CF₃ or    (C₃₋₇)cycloalkyl and wherein the groups X and R′ are attached to    positions on the Ar ring which are immediately adjacent to each    other;-   X is selected from O and S;-   R¹ is a group of formula:

-   R¹¹ is halo; and-   R¹², R¹³, R¹⁴ and R¹⁵ are each independently selected from H, halo,    (C₁₋₄)alkyl, CF₃, (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-,    cyano, —O—(C₁₋₄)alkyl, —OCF₃ and —N((C₁₋₄)alkyl)₂, wherein said    (C₃₋₇)cycloalkyl is optionally substituted with (C₁₋₄)alkyl; or-   R¹² and R¹³, R¹³ and R¹⁴, or R¹⁴ and R¹⁵ are linked, together with    the carbon atoms to which they are attached, to form a five- or    six-membered saturated, unsaturated or aromatic ring which    optionally contains from one to three heteroatoms each independently    selected from O, S and N, wherein the remaining of R¹², R¹³, R¹⁴ and    R¹⁵ are defined as hereinbefore;-   R² is selected from halo, nitro and (C₁₋₄)alkyl;-   R³ is selected from H and halo;-   R⁴ is selected from:-   a)

wherein R⁴² is bonded to position 2 or position 3 of the phenyl ring andis selected from H, halo and (C₁₋₄)alkyl; and R⁴¹ is bonded to position3 or position 4 of the phenyl ring and is selected from:

-   -   i) (C₁₋₄)alkyl substituted with —COOH, —COO(C₁₋₄)alkyl,        —C(═O)NH₂, —C(═O)NHSO₂-(C₁₋₄)alkyl, or —OH;    -   ii) (C₂₋₄)alkenyl substituted with —COOH or —COO(C₁₋₄)alkyl;    -   iii) —O—(C₁₋₄)alkyl optionally substituted with —COOH, Het, or        —N((C₁₋₆)alkyl)₂, wherein said Het is optionally substituted        with —OH or —COOH and wherein either or both of the (C₁₋₆)alkyl        groups in said —N((C₁₋₆)alkyl)₂ are optionally substituted with        —COOH or —COO(C₁₋₄)alkyl; and    -   iv) —OH, —COOH, —COO(C₁₋₄)alkyl, —SO₂NH₂, or —SO₂—(C₁₋₄)alkyl;    -   provided that R⁴² and R⁴¹ may not both be bonded to position 3        of the phenyl ring at the same time;

-   b) (C₂₋₄)alkenyl substituted with —COOH or —COO(C₁₋₄)alkyl;

-   c) Het optionally substituted with (C₁₋₆)alkyl, —NH₂, —COOH, or    (C₂₋₄)alkenyl substituted with —COOH;

-   d) —SO₂N(R⁴³)R⁴⁴, wherein R⁴³ is H or (C₁₋₆)alkyl and R⁴⁴ is    selected from (C₁₋₆)alkyl, phenyl, phenyl-(C₁₋₄)alkyl-,    —C(═O)NH(C₁₋₄)alkyl, —C(═O)O(C₁₋₄)alkyl, and Het; wherein said    (C₁₋₆)alkyl is optionally substituted with —OH or —COOH and wherein    said Het is optionally substituted with (C₁₋₆)alkyl;    -   or R⁴³ and R⁴⁴, together with the N to which they are attached,        are linked together to form a 5- or 6-membered heterocycle which        may be saturated or unsaturated and which may optionally contain        from one to three further heteroatoms each independently        selected from N, O and S; said heterocycle being optionally        substituted with (C₁₋₆)alkyl or —COOH;

-   e) —O—(C₁₋₄)alkyl substituted with —OH, —COOH or Het, wherein said    Het is optionally substituted with —COOH or —COO(C₁₋₆)alkyl;

-   f) —C(═O)N(R⁵)R⁶ or —O—CH₂—C(═O)N(R⁵)R⁶ wherein R⁵ is H or    (C₁₋₆)alkyl and R⁶ is selected from:    -   i) phenyl optionally substituted with one or two substituents        each independently selected from —OH, —COOH, —N((C₁₋₄)alkyl)₂,        (C₁₋₄)alkyl, (C₂₋₄)alkenyl and Het; wherein said (C₁₋₄)alkyl is        optionally substituted with —COOH and said (C₂₋₄)alkenyl is        substituted with —COOH;    -   ii) (C₁₋₄)alkyl optionally substituted with one or two        substituents each independently selected from —COOH, —OH,        —S—(C₁₋₆)alkyl and Het;    -   iii) phenyl-(C₁₋₄)alkyl- wherein the phenyl portion of said        phenyl-(C₁₋₄)alkyl- is optionally substituted with one or two        substituents each independently selected from —OH, —NH₂, and        —COOH;    -   iv) (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl- wherein the cycloalkyl portion        of said (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl- is optionally substituted        with —COOH;    -   v) Het optionally substituted with one or two substituents each        independently selected from (C₁₋₆)alkyl, phenyl-(C₁₋₄)alkyl- and        —COOH;    -   vi) (C₃₋₇)cycloalkyl; and    -   vii) —SO₂—R⁶¹ wherein R⁶¹ is (C₁₋₄)alkyl or phenyl;    -   or R⁵ and R⁶, together with the N to which they are attached,        are linked together to form a 5- or 6-membered heterocycle which        may be saturated or unsaturated and which may optionally contain        from one to three further heteroatoms each independently        selected from N, O and S; said heterocycle being optionally        substituted with one or two substituents each independently        selected from (C₁₋₆)alkyl, —COOH and —COO(C₁₋₆)alkyl;

-   g) —NHC(═O)—R⁷ wherein R⁷ is selected from:    -   i) (C₁₋₆)alkyl optionally substituted with one or two        substituents each independently selected from —COOH,        —O—(C₁₋₄)alkyl, —NHC(═O)—(C₁₋₄)alkyl, phenyl and Het; wherein        said phenyl is optionally substituted with one or two        substituents each independently selected from halo, —OH,        —O—(C₁₋₄)alkyl, —NO₂, —COOH, —NH₂, —NH(C₁₋₄)alkyl,        —N((C₁₋₄)alkyl)₂, and (C₁₋₆)alkyl optionally substituted with        from one to three halo substituents;    -   ii) phenyl optionally substituted with —OH, halo or —COOH;    -   iii) —NHR⁷¹ wherein R⁷¹ is phenyl or phenyl-(C₁₋₄)alkyl-,        wherein said phenyl is optionally substituted with —COOH or        —COO(C₁₋₄)alkyl; and    -   iv) (C₁₋₆)alkynyl, (C₃₋₇)cycloalkyl or        (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-;

-   h) —NHSO₂R⁸ wherein R⁸ is selected from phenyl, phenyl-(C₁₋₄)alkyl-    and Het; and

-   i) —C≡C—R⁹ wherein R⁹ is selected from:    -   i) H, —COOH, —COO(C₁₋₁₆)alkyl, phenyl or (C₂₋₄)alkenyl;    -   ii) (C₃₋₇)cycloalkyl optionally substituted with —OH, —COOH,        —COO(C₁₋₆)alkyl, or (C₁₋₄)alkyl wherein said (C₁₋₄)alkyl is        optionally substituted with —OH or —N(R⁹¹)R⁹², wherein R⁹¹ is H        and R⁹² is (C₁₋₄)alkyl substituted with Het; or R⁹¹ and R⁹²,        together with the N to which they are attached, are linked        together to form a 5- or 6-membered heterocycle which may be        saturated, unsaturated or aromatic and which may optionally        contain from one to three further heteroatoms each independently        selected from N, O and S; said heterocycle being optionally        substituted with one or two substituents each independently        selected from (C₁₋₆)alkyl and —OH; and    -   iii) (C₁₋₆)alkyl optionally substituted with one, two or three        substituents each independently selected from:        -   a) —OH, —O(C═O)NH₂, —O(C═O)NH(C₁₋₄)alkyl, CF₃, —COOH or            —COO—(C₁₋₄)alkyl;        -   b) Het optionally substituted with (C₁₋₆)alkyl or —OH;        -   c) —N(R⁹³)R⁹⁴ wherein R⁹³ is H or (C₁₋₄)alkyl and R⁹⁴ is            selected from H, —(C₁₋₄)alkyl optionally substituted with            R⁹⁴¹, —SO₂—(C₁₋₄)alkyl and —C(═O)—R⁹⁴²;            -   wherein R⁹⁴¹ is —COOH, —C(═O)NH₂, (C₃₋₇)cycloalkyl, Het,                or phenyl optionally substituted with —OH,            -   and R⁹⁴² is —O—(C₁₋₄)alkyl, —NH—(C₁₋₄)alkyl, phenyl,                (C₃₋₇)cycloalkyl or Het, wherein said (C₃₋₇)cycloalkyl                is optionally substituted with —COOH and wherein said                Het is optionally substituted with one or two                substituents each independently selected from                (C₁₋₆)alkyl and —OH; or            -   R⁹⁴² is (C₁₋₄)alkyl optionally substituted with —COOH,                —NH₂, —NH(C₁₋₄)alkyl, —NH-Het, —N((C₁₋₄)alkyl)₂, or Het;                wherein said Het is optionally substituted with one or                two substituents each independently selected from —OH,                —COOH and (C₁₋₆)alkyl optionally substituted with Het                and wherein the (C₁₋₄)alkyl portion of said                —NH(C₁₋₄)alkyl is optionally substituted with Het;        -   d) —C(═O)N(R⁹⁵)R⁹⁶, wherein R⁹⁵ is H and R⁹⁶ is selected            from (C₃₋₇)cycloalkyl, —SO₂—R⁹⁶¹ and —(C₁₋₄)alkyl-R⁹⁶²,            wherein            -   R⁹⁶¹ is (C₁₋₄)alkyl, phenyl, (C₃₋₇)cycloalkyl, or                —N((C₁₋₄)alkyl)₂; and            -   R⁹⁶² is phenyl, —COOH, —N((C₁₋₄)alkyl)₂, or Het, wherein                said phenyl is optionally substituted with                —N((C₁₋₄)alkyl)₂ and said Het is optionally substituted                with oxo;            -   or R⁹⁵ and R⁹⁶, together with the N to which they are                attached, are linked together to form a 5- or 6-membered                heterocycle which may be saturated or unsaturated and                which may optionally contain from one to three further                heteroatoms each independently selected from N, O and S;                said heterocycle being optionally substituted with                —COOH; and        -   e) —O(C₁₋₄)alkyl optionally substituted with R⁹⁷ wherein R⁹⁷            is selected from —OH, —COOH,            —C(═O)O—(C₁₋₄)alkyl-NH(C₁₋₄)alkyl, —C(═O)N(R⁹⁷¹)R⁹⁷², —NH₂,            —NH—(C₃₋₇)cycloalkyl, —O-Het, and Het wherein said Het is            optionally substituted with one or two substituents each            independently selected from halo, oxo, (C₁₋₄)alkyl, and —OH;            -   wherein R⁹⁷¹ is H or (C₁₋₄)alkyl and R⁹⁷² is selected                from H, —OH, —NHC(═O)—(C₁₋₄)alkyl, —NHC(═O)—NH₂,                (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl, phenyl and Het, wherein                said (C₁₋₄)alkyl is optionally substituted with —OH,                —COOH, —N((C₁₋₄)alkyl)₂ or Het, and wherein said                (C₃₋₇)cycloalkyl is optionally substituted with —COOH,                and wherein said phenyl is optionally substituted with                —OH, —COOH, or —(C₂₋₄)alkenyl-COOH;            -   or R⁹⁷¹ and R⁹⁷², together with the N to which they are                attached, are linked together to form a 5- or 6-membered                heterocycle which may be saturated or unsaturated and                which may optionally contain from one to three further                heteroatoms each independently selected from N, O and S;                said heterocycle being optionally substituted with                (C₁₋₄)alkyl or —COOH;                wherein Het is a 5- or 6-membered heterocycle or a 9- or                10-membered heterobicycle, each of which may be                saturated, unsaturated or aromatic and each of which may                optionally contain from one to four heteroatoms each                independently selected from N, O and S, wherein each                said N heteroatom may, independently and where possible,                exist in an oxidized state such that it is further                bonded to an O atom to form an N-oxide group and wherein                each said S heteroatom may, independently and where                possible, exist in an oxidized state such that it is                further bonded to one or two oxygen atoms to form the                groups SO or SO₂;                or an enantiomer, diastereoisomer or tautomer thereof,                or a pharmaceutically acceptable salt or ester thereof.

A preferred embodiment provides a compound of formula (I) wherein:

-   Ar is selected from:

-   -   wherein R^(Ar) is selected from H, CH₃, CF₃ and cyclopropyl and        wherein the designation

represents the bond to R¹ and the designation

represents the bond to X;

-   X is S;-   R¹ is a group of formula:

-   R¹¹ is chloro or bromo;-   R¹² is selected from H, (C₁₋₄)alkyl, CF₃, (C₃₋₇)cycloalkyl and halo;-   R¹³ is selected from H, (C₁₋₄)alkyl, CF₃, (C₃₋₇)cycloalkyl,    (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-, —O—(C₁₋₄)alkyl, —N((C₁₋₄)alkyl)₂ and    —CF₃; wherein the (C₃₋₇)cycloalkyl is optionally substituted with    (C₁₋₄)alkyl;-   R¹⁴ is selected from H, halo, cyano, (C₁₋₄)alkyl, CF₃,    (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-, —O—(C₁₋₄)alkyl, and    —N((C₁₋₄)alkyl)₂;-   or R¹² and R¹³ or R¹³ and R¹⁴ are linked, together with the carbon    atoms to which they are attached, to form a five- or six-membered    saturated, unsaturated or aromatic ring which optionally contains    from one to three heteroatoms each independently selected from O, S    and N;-   R¹⁵ is selected from H, halo, (C₁₋₄)alkyl and CF₃;-   R² is selected from halo, nitro and methyl;-   R³ is H or fluoro; and-   R⁴ is

wherein R⁴² is bonded to position 2 or position 3 of the phenyl ring andis selected from H, halo and (C₁₋₄)alkyl; and R⁴¹ is bonded to position3 or position 4 of the phenyl ring and is selected from:

-   -   i) (C₁₋₄)alkyl substituted with —COOH, —COO(C₁₋₄)alkyl,        —C(═O)NH₂, —C(═O)NHSO₂—(C₁₋₄)alkyl, or —OH;    -   ii) (C₂₋₄)alkenyl substituted with —COOH or —COO(C₁₋₄)alkyl;    -   iii) —O—(C₁₋₄)alkyl optionally substituted with —COOH, Het, or        —N((C₁₋₆)alkyl)₂, wherein Het is a 5- or 6-membered saturated,        unsaturated or aromatic monocyclic heterocycle containing 1 to 4        heteroatoms each independently selected from O, S and N, wherein        each said S heteroatom may, independently and where possible,        exist in an oxidized state such that it is further bonded to one        or two oxygen atoms to form the groups SO or SO₂, said Het being        optionally substituted with —OH or —COOH; and wherein either or        both of the (C₁₋₆)alkyl groups in said —N((C₁₋₆)alkyl)₂ are        optionally substituted with —COOH or —COO(C₁₋₄)alkyl; and    -   iv) —OH, —COOH, —COO(C₁₋₄)alkyl, —SO₂NH₂, or —SO₂-(C₁₋₄)alkyl;    -   provided that R⁴² and R⁴¹ may not both be bonded to position 3        of the phenyl ring at the same time.

An alternative preferred embodiment provides a compound of formula (I)wherein:

-   Ar is selected from:

-   -   wherein R^(Ar) is selected from H, CH₃, CF₃ and cyclopropyl and        wherein the designation

represents the bond to R¹ and the designation

represents the bond to X;

-   X is S;-   R¹ is a group of formula:

-   R¹¹ is chloro or bromo;-   R¹² is selected from H, (C₁₋₄)alkyl, CF₃, (C₃₋₇)cycloalkyl and halo;-   R¹³ is selected from H, (C₁₋₄)alkyl, CF₃, (C₃₋₇)cycloalkyl,    (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-, —O—(C₁₋₄)alkyl, —N((C₁₋₄)alkyl)₂ and    —OCF₃; wherein the (C₃₋₇)cycloalkyl is optionally substituted with    (C₁₋₄)alkyl;-   R¹⁴ is selected from H, halo, cyano, (C₁₋₄)alkyl, CF₃,    (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-, —O—(C₁₋₄)alkyl, and    —N((C₁₋₄)alkyl)₂;-   or R¹² and R¹³ or R¹³ and R¹⁴ are linked, together with the carbon    atoms to which they are attached, to form a five- or six-membered    saturated, unsaturated or aromatic ring which optionally contains    from one to three heteroatoms each independently selected from O, S    and N;-   R¹⁶ is selected from H, halo, (C₁₋₄)alkyl and CF₃;-   R² is selected from halo, nitro and methyl;-   R³ is H or fluoro; and-   R⁴ is selected from:-   b) (C₂₋₄)alkenyl substituted with —COOH or —COO(C₁₋₄)alkyl;-   c) Het optionally substituted with (C₁₋₆)alkyl, —NH₂, —COOH, or    (C₂₋₄)alkenyl substituted with —COOH, wherein Het is a 5- or    6-membered aromatic monocyclic heterocycle containing 1 to 4    heteroatoms each independently selected from O, S and N;-   d) —SO₂N(R⁴³)R⁴⁴, wherein R⁴³ is H or (C₁₋₆)alkyl and R⁴⁴ is    selected from (C₁₋₆)alkyl, phenyl, phenyl-(C₁₋₄)alkyl-,    —C(═O)NH(C₁₋₄)alkyl, —C(═O)O(C₁₋₄)alkyl, and Het wherein Het is a 5-    or 6-membered saturated, unsaturated or aromatic monocyclic    heterocycle containing 1 to 4 heteroatoms each independently    selected from O, S and N; wherein said (C₁₋₆)alkyl is optionally    substituted with —OH or —COOH and wherein said Het is optionally    substituted with (C₁₋₆)alkyl;    -   or R⁴³ and R⁴⁴, together with the N to which they are attached,        are linked together to form a 5- or 6-membered heterocycle which        may be saturated or unsaturated and which may optionally contain        from one to three further heteroatoms each independently        selected from N, O and S; said heterocycle being optionally        substituted with (C₁₋₆)alkyl or —COOH;-   e) —O—(C₁₋₄)alkyl substituted with —OH, —COOH or Het wherein Het is    a 5- or 6-membered saturated, unsaturated or aromatic monocyclic    heterocycle containing 1 to 4 heteroatoms each independently    selected from O, S and N, wherein said Het is optionally substituted    with —COOH or —COO(C, r)alkyl; provided that the carbon atom of    —O—(C₁₋₄)alkyl which is directly bonded to 0 is not also directly    bonded to —OH; and-   h) —NHSO₂R⁸ wherein R⁸ is selected from phenyl, phenyl-(C₁₋₄)alkyl-    and Het wherein Het is a 5- or 6-membered saturated, unsaturated or    aromatic monocyclic heterocycle containing 1 to 4 heteroatoms each    independently selected from O, S and N.

Another alternative preferred embodiment provides a compound of formula(I) wherein:

-   Ar is selected from:

-   -   wherein R^(Ar) is selected from H, CH₃, CF₃ and cyclopropyl and        wherein the designation

represents the bond to R¹ and the designation

represents the bond to X;

-   X is S;-   R¹ is a group of formula:

-   R¹¹ is chloro or bromo;-   R¹² is selected from H, (C₁₋₄)alkyl, CF₃, (C₃₋₇)cycloalkyl and halo;-   R¹³ is selected from H, (C₁₋₄)alkyl, CF₃, (C₃₋₇)cycloalkyl,    (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-, —O—(C₁₋₄)alkyl, —N((C₁₋₄)alkyl)₂ and    —OCF₃; wherein the (C₃₋₇)cycloalkyl is optionally substituted with    (C₁₋₄)alkyl;-   R¹⁴ is selected from H, halo, cyano, (C₁₋₄)alkyl, CF₃,    (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-, —O—(C₁₋₄)alkyl, and    —N((C₁₋₄)alkyl)₂;-   or R¹² and R¹³ or R¹³ and R¹⁴ are linked, together with the carbon    atoms to which they are attached, to form a five- or six-membered    saturated, unsaturated or aromatic ring which optionally contains    from one to three heteroatoms each independently selected from O, S    and N;-   R¹⁵ is selected from H, halo, (C₁₋₄)alkyl and CF₃;-   R² is selected from halo, nitro and methyl;-   R³ is H or fluoro; and-   R⁴ is —C(═O)N(R⁵)R⁶ or —O—CH₂—C(═O)N(R⁵)R⁶ wherein R⁵ is H or    (C₁₋₆)alkyl and R⁶ is selected from:    -   i) phenyl optionally substituted with one or two substituents        each independently selected from —OH, —COOH, —N((C₁₋₄)alkyl)₂,        (C₁₋₄)alkyl, (C₂₋₄)alkenyl and Het wherein Het is a 5- or        6-membered saturated, unsaturated or aromatic monocyclic        heterocycle containing 1 to 4 heteroatoms each independently        selected from O, S and N; wherein said (C₁₋₄)alkyl is optionally        substituted with —COOH and said (C₂₋₄)alkenyl is substituted        with —COOH;    -   ii) (C₁₋₄)alkyl optionally substituted with one or two        substituents each independently selected from —COOH, —OH,        —S—(C₁₋₆)alkyl and Het wherein Het is a 5- or 6-membered        saturated, unsaturated or aromatic monocyclic heterocycle        containing 1 to 4 heteroatoms each independently selected from        O, S and N wherein each said N heteroatom may, independently and        where possible, exist in an oxidized state such that it is        further bonded to an O atom to form an N-oxide group;        -   provided that the carbon atom of (C₁₋₄)alkyl which is            directly bonded to N is not also directly bonded to —OH;    -   iii) phenyl-(C₁₋₄)alkyl- wherein the phenyl portion of said        phenyl-(C₁₋₄)alkyl- is optionally substituted with one or two        substituents each independently selected from —OH, —NH₂ and        —COOH;    -   iv) (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl- wherein the cycloalkyl portion        of said (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl- is optionally substituted        with —COOH;    -   v) Het optionally substituted with one or two substituents each        independently selected from (C₁₋₆)alkyl, phenyl-(C₁₋₄)alkyl- and        —COOH wherein Het is a 5- or 6-membered heterocycle or a 9- or        10-membered heterobicycle, each of which may be saturated,        unsaturated or aromatic and each of which may optionally contain        from one to four heteroatoms each independently selected from N,        O and S;    -   vi) (C₃₋₇)cycloalkyl; and    -   vii)-SO₂—R⁶¹ wherein R⁶¹ is (C₁₋₄)alkyl or phenyl;    -   or R⁵ and R⁶, together with the N to which they are attached,        are linked together to form a 5- or 6-membered heterocycle which        may be saturated or unsaturated and which may optionally contain        from one to three further heteroatoms each independently        selected from N, O and S; said heterocycle being optionally        substituted with one or two substituents each independently        selected from (C₁₋₆)alkyl, —COOH and —COO(C₁₋₆)alkyl.

Yet another alternative preferred embodiment provides a compound offormula (I) wherein:

-   Ar is selected from:

-   -   wherein R^(Ar) is selected from H, CH₃, CF₃ and cyclopropyl and        wherein the designation

represents the bond to R¹ and the designation

represents the bond to X;

-   X is S;-   R¹ is a group of formula:

-   R¹¹ is chloro or bromo;-   R¹² is selected from H, (C₁₋₄)alkyl, CF₃, (C₃₋₇)cycloalkyl and halo;-   R¹³ is selected from H, (C₁₋₄)alkyl, CF₃, (C₃₋₇)cycloalkyl,    (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-, —O—(C₁₋₄)alkyl, —N((C₁₋₄)alkyl)₂ and    —OCF₃; wherein the (C₃₋₇)cycloalkyl is optionally substituted with    (C₁₋₄)alkyl;-   R¹⁴ is selected from H, halo, cyano, (C₁₋₄)alkyl, CF₃,    (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-, —O—(C₁₋₄)alkyl, and    —N((C₁₋₄)alkyl)₂;-   or R¹² and R¹³ or R¹³ and R¹⁴ are linked, together with the carbon    atoms to which they are attached, to form a five- or six-membered    saturated, unsaturated or aromatic ring which optionally contains    from one to three heteroatoms each independently selected from O, S    and N;-   R¹⁵ is selected from H, halo, (C₁₋₄)alkyl and CF₃;-   R² is selected from halo, nitro and methyl;-   R³ is H or fluoro; and-   R⁴ is —NHC(═O)—R⁷ wherein R⁷ is selected from:    -   i) (C₁₋₆)alkyl optionally substituted with one or two        substituents each independently selected from —COOH,        —O—(C₁₋₄)alkyl, —NHC(═O)—(C₁₋₄)alkyl, phenyl and Het wherein Het        is a 5- or 6-membered heterocycle or a 9- or 10-membered        heterobicycle, each of which may be saturated, unsaturated or        aromatic and each of which may optionally contain from one to        four heteroatoms each independently selected from N, O and S        wherein each said N heteroatom may, independently and where        possible, exist in an oxidized state such that it is further        bonded to an O atom to form an N-oxide group; and wherein said        phenyl is optionally substituted with one or two substituents        each independently selected from halo, —OH, —O—(C₁₋₄)alkyl,        —NO₂, —COOH, —NH₂, —NH(C₁₋₄)alkyl, —N((C₁₋₄)alkyl)₂, and        (C₁₋₆)alkyl optionally substituted with from one to three halo        substituents;    -   ii) phenyl optionally substituted with —OH, halo or —COOH;    -   iii) —NHR⁷¹ wherein R⁷¹ is phenyl or phenyl-(C₁₋₄)alkyl-,        wherein said phenyl is optionally substituted with —COOH or        —COO(C₁₋₄)alkyl; and    -   iv) (C₁₋₆)alkynyl, (C₃₋₇)cycloalkyl or        (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-.

Still another alternative preferred embodiment provides a compound offormula (I) wherein:

-   Ar is selected from:

wherein R^(Ar) is selected from H, CH₃, CF₃ and cyclopropyl and whereinthe designation

represents the bond to R¹ and the designation

represents the bond to X;

-   X is S;-   R¹ is a group of formula:

-   R¹¹ is chloro or bromo;-   R¹² is selected from H, (C₁₋₄)alkyl, CF₃, (C₃₋₇)cycloalkyl and halo;-   R¹³ is selected from H, (C₁₋₄)alkyl, CF₃, (C₃₋₇)cycloalkyl,    (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-, —O—(C₁₋₄)alkyl, —N((C₁₋₄)alkyl)₂ and    —OCF₃; wherein the (C₃₋₇)cycloalkyl is optionally substituted with    (C₁₋₄)alkyl;-   R¹⁴ is selected from H, halo, cyano, (C₁₋₄)alkyl, CF₃,    (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-, —O—(C₁₋₄)alkyl, and    —N((C₁₋₄)alkyl)₂;-   or R¹² and R¹³ or R¹³ and R¹⁴ are linked, together with the carbon    atoms to which they are attached, to form a five- or six-membered    saturated, unsaturated or aromatic ring which optionally contains    from one to three heteroatoms each independently selected from O, S    and N;-   R¹⁵ is selected from H, halo, (C₁₋₄)alkyl and CF₃;-   R² is selected from halo, nitro and methyl;-   R³ is H or fluoro; and-   R⁴ is —C≡C—R⁹ wherein R⁹ is selected from:    -   i) H, —COOH, —COO(C₁₋₆)alkyl, phenyl or (C₂₋₄)alkenyl;    -   ii) (C₃₋₇)cycloalkyl optionally substituted with —OH, —COOH,        —COO(C₁₋₆)alkyl, or (C₁₋₄)alkyl wherein said (C₁₋₄)alkyl is        optionally substituted with —OH or —N(R⁹¹)R⁹², wherein R⁹¹ is H        and R⁹² is (C₁₋₄)alkyl substituted with Het; or R⁹¹ and R⁹²,        together with the N to which they are attached, are linked        together to form a 5- or 6-membered heterocycle which may be        saturated, unsaturated or aromatic and which may optionally        contain from one to three further heteroatoms each independently        selected from N, O and S; said heterocycle being optionally        substituted with one or two substituents each independently        selected from (C₁₋₆)alkyl and —OH; and    -   iii) (C₁₋₆)alkyl optionally substituted with one, two or three        substituents each independently selected from:        -   a) —OH, —O(C═O)NH₂, —O(C═O)NH(C₁₋₄)alkyl, CF₃, —COOH or            —COO—(C₁₋₄)alkyl;        -   b) Het optionally substituted with (C₁₋₆)alkyl or —OH;        -   c) —N(R⁹³)R⁹⁴ wherein R⁹³ is H or (C₁₋₄)alkyl and R⁹⁴ is            selected from H, —(C₁₋₄)alkyl optionally substituted with            R⁹⁴¹, —SO₂-(C₁₋₄)alkyl and —C(═O)—R⁹⁴²;            -   wherein R⁹⁴¹ is —COOH, —C(═O)NH₂, (C₃₋₇)cycloalkyl, Het,                or phenyl optionally substituted with —OH,            -   and R⁹⁴² is —O—(C₁₋₄)alkyl, —NH—(C₁₋₄)alkyl, phenyl,                (C₃₋₇)cycloalkyl or Het, wherein said (C₃₋₇)cycloalkyl                is optionally substituted with —COOH and wherein said                Het is optionally substituted with one or two                substituents each independently selected from                (C₁₋₆)alkyl and —OH; or            -   R⁹⁴² is (C₁₋₄)alkyl optionally substituted with —COOH,                —NH₂, —NH(C₁₋₄)alkyl, —NH-Het, —N((C₁₋₄)alkyl)₂, or Het;                wherein said Het is optionally substituted with one or                two substituents each independently selected from —OH,                —COOH and (C₁₋₆)alkyl optionally substituted with Het                and wherein the (C₁₋₄)alkyl portion of said                —NH(C₁₋₄)alkyl is optionally substituted with Het;        -   d) —C(═O)N(R⁹⁵)R⁹⁶, wherein R⁹⁵ is H and R⁹⁶ is selected            from (C₃₋₇)cycloalkyl, —SO₂—R⁹⁶′ and —(C₁₋₄)alkyl-R⁹⁶²,            wherein            -   R⁹⁶¹ is (C₁₋₄)alkyl, phenyl, (C₃₋₇)cycloalkyl, or                —N((C₁₋₄)alkyl)₂; and            -   R⁹⁶² is phenyl, —COOH, —N((C₁₋₄)alkyl)₂, or Het, wherein                said phenyl is optionally substituted with                —N((C₁₋₄)alkyl)₂ and said Het is optionally substituted                with oxo;            -   or R⁹⁵ and R⁹⁶, together with the N to which they are                attached, are linked together to form a 5- or 6-membered                heterocycle which may be saturated or unsaturated and                which may optionally contain from one to three further                heteroatoms each independently selected from N, O and S;                said heterocycle being optionally substituted with                —COOH; and        -   e) —O(C₁₋₄)alkyl optionally substituted with R⁹⁷ wherein R⁹⁷            is selected from —OH, —COOH,            —C(═O)O—(C₁₋₄)alkyl-NH(C₁₋₄)alkyl, —C(═O)N(R⁹⁷¹)R⁹⁷², —NH₂,            —NH—(C₃₋₇)cycloalkyl, —O-Het, and Het;            -   provided that the carbon atom of —O—(C₁₋₄)alkyl which is                directly bonded to 0 is not also directly bonded to —OH,                —NH₂ or —NH—(C₃₋₇)cycloalkyl;            -   wherein each of said Het and the Het portion of said                —O-Het is optionally substituted with one or two                substituents each independently selected from halo, oxo,                (C₁₋₄)alkyl, and —OH; and            -   wherein R⁹⁷¹ is H or (C₁₋₄)alkyl and R⁹⁷² is selected                from H, —OH, —NHC(═O)—(C₁₋₄)alkyl, —NHC(═O)—NH₂,                (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl, phenyl and Het, wherein                said (C₁₋₄)alkyl is optionally substituted with —OH,                —COOH, —N((C₁₋₄)alkyl)₂ or Het, provided that when R⁹⁷²                is (C₁₋₄)alkyl, the carbon atom of (C₁₋₄)alkyl which is                directly bonded to N is not also directly bonded to —OH;            -   and wherein said (C₃₋₇)cycloalkyl is optionally                substituted with —COOH, and wherein said phenyl is                optionally substituted with —OH, —COOH, or                —(C₂₋₄)alkenyl-COOH;            -   or R⁹⁷¹ and R⁹⁷², together with the N to which they are                attached, are linked together to form a 5- or 6-membered                heterocycle which may be saturated or unsaturated and                which may optionally contain from one to three further                heteroatoms each independently selected from N, O and S;                said heterocycle being optionally substituted with                (C₁₋₄)alkyl or —COOH;                wherein Het is in each instance independently a 4,5- or                6-membered saturated, unsaturated or aromatic monocyclic                heterocycle containing from one to four heteroatoms each                independently selected from N, O and S, wherein each                said N heteroatom may, independently and where possible,                exist in an oxidized state such that it is further                bonded to an O atom to form an N-oxide group and wherein                each said S heteroatom may, independently and where                possible, exist in an oxidized state such that it is                further bonded to one or two oxygen atoms to form the                groups SO or SO₂.

A more preferred embodiment provides a compound of formula (Ia)

wherein

-   X is S;-   R¹ is selected from:

-   R² is chloro;-   R³ is H or fluoro; and-   R⁴ is

wherein R⁴² is bonded to position 2 or position 3 of the phenyl ring andis selected from H, Cl, F and CH₃; and R⁴¹ is bonded to position 4 ofthe phenyl ring and is selected from:

-   -   i) methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,        2-methylpropyl and 1,1-dimethylethyl, each of which being        substituted with —COOH, —COOCH₃, —COOCH₂CH₃—C(═O)NH₂,    -   —C(═O)NHSO₂—CH₃, or —OH;    -   ii) —CH═CH—COOH, —CH═CH—COOCH₃ or —CH═CH—COOCH₂CH₃;    -   iii) —O—CH₃ or —O—CH₂CH₃, each of which being optionally        substituted with —COOH, Het, or —N((C₁₋₄)alkyl)₂, wherein Het is        selected from

wherein said Het is optionally substituted with —OH or —COOH and whereineither or both of the (C₁₋₄)alkyl groups in said —N((C₁₋₄)alkyl)₂ areoptionally substituted with —COOH, —COOCH₃ or —COOCH₂CH₃; and

-   -   iv) —OH, —COOH, —COOCH₃, —COOCH₂CH₃, —SO₂NH₂, or —SO₂—CH₃.

An alternative more preferred embodiment provides a compound of formula(Ia)

wherein

-   X is S;-   R¹ is selected from:

-   R² is chloro;-   R³ is H or fluoro; and-   R⁴ is —C(═O)N(R⁵)R⁶ wherein R⁵ is H or CH₃ and R⁶ is selected from    -   i) phenyl optionally substituted with one or two substituents        each independently selected from —OH, —COOH, —N(CH₃)₂, CH₃,        —CH₂COOH, —CH₂CH₂COOH,

-   -   ii) (C₁₋₄)alkyl optionally substituted with one or two        substituents each independently selected from —COOH, —OH, —S—CH₃        and Het, wherein Het is selected from

provided that the carbon atom of (C₁₋₄)alkyl which is directly bonded toN is not also directly bonded to —OH;

-   -   iii) phenyl-CH₂— or phenyl-CH₂CH₂—, wherein the phenyl portion        of said phenyl-CH₂— or phenyl-CH₂CH₂— is optionally substituted        with one or two substituents each independently selected from        —OH, —NH₂, and —COOH;    -   iv) (4-carboxycyclohexyl)methyl;    -   v) Het optionally substituted with one or two substituents each        independently selected from methyl, phenylmethyl- and —COOH,        wherein said Het is selected from

-   -   vi) cyclopropyl;    -   vii)-SO₂—CH₃ and —SO₂-Ph;        or R⁶ and R⁶, together with the N to which they are attached,        are linked together to form a 6-membered saturated heterocycle        which may optionally contain one further heteroatom        independently selected from N and O; said heterocycle being        optionally substituted with one or two substituents each        independently selected from CH₃ and —COOH.

Another alternative more preferred embodiment provides a compound offormula (Ia)

wherein

-   X is S;-   R¹ is selected from:

-   R² is chloro;-   R³ is H or fluoro; and-   R⁴ is —NHC(═O)—R⁷ wherein R⁷ is selected from:    -   i) methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,        2-methylpropyl, 1,1-dimethylethyl, 1-methylbutyl, 2-methylbutyl        or 3methylbutyl, each of which being optionally substituted with        one or two substituents each independently selected from

and wherein said phenyl is optionally substituted with one or twosubstituents each independently selected from halo, —OH, —O—CH₃, —NO₂,—COOH, —NH₂, —NHCH₃, —N(CH₃)₂, and CF₃;

-   -   ii) phenyl optionally substituted with —OH, Cl or —COOH;    -   iii) —NH-phenyl or phenyl-CH₂—NH—, wherein the phenyl portion of        said —NH-phenyl and phenyl-CH₂—NH— is optionally substituted        with —COOH, —COOCH₃ or —COOCH₂CH₃; and    -   iv) ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,        3-butynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl        cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or        cyclohexylmethyl.

Still another alternative more preferred embodiment provides a compoundof formula (Ia)

wherein

-   X is S;-   R¹ is selected from:

-   R² is chloro;-   R³ is H or fluoro; and-   R⁴ is —C═C—R⁹ wherein R⁹ is selected from:    -   i) H, —COOH, phenyl, ethenyl or 2-propenyl;    -   ii) cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of        which being optionally substituted with —OH, —COOH or CH₃,        wherein said CH₃ is optionally substituted with —OH or        —N(R⁹¹)R⁹², wherein R⁹¹ is H and R⁹² is

or R⁹¹ and R⁹², together with the N to which they are attached, arelinked together to form a 5- or 6-membered heterocycle which may besaturated, unsaturated or aromatic and which may optionally contain oneor two further heteroatoms each independently selected from N and O;said heterocycle being optionally substituted with one or twosubstituents each independently selected from CH₃ and —OH;

-   -   iii) methyl, ethyl, propyl, 1-methylethyl, butyl,        1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl or        1-ethylpropyl, each of which being optionally substituted with        one, two or three substituents each independently selected from:        -   a) —OH, —O(C═O)NH₂, —O(C═O)NHCH₃, CF₃, —COOH, —COOCH₃ or            —COOCH₂CH₃;        -   b) Het optionally substituted with CH₃ or —OH; wherein Het            is selected from

-   -   -   c) —N(R⁹³)R⁹⁴ wherein R⁹³ is H, CH₃ or CH₂CH₃ and R⁹⁴ is            selected from H, —(C₁₋₄)alkyl optionally substituted with            R⁹⁴¹, —SO₂—CH₃ and —C(═O)—R⁹⁴²;            -   wherein R⁹⁴¹ is —COOH, —C(═O)NH₂, cyclopropyl, Het, or                phenyl optionally substituted with —OH; wherein Het is                selected from

-   -   -   -   R⁹⁴² is —O—(C₁₋₄)alkyl, —NH—(C₁₋₄)alkyl, phenyl,                cyclopropyl or Het; wherein Het is selected from

and wherein said cyclopropyl is optionally substituted with —COOH andwherein said Het is optionally substituted with CH₃ or —OH; or

-   -   -   -   R⁹⁴² is (C₁₋₄)alkyl optionally substituted with —COOH,                —NH₂, —NH(C₁₋₄)alkyl,

—N((C₁₋₄)alkyl)₂ or Het; wherein Het is selected from

and wherein said Het is optionally substituted with one or twosubstituents each independently selected from —OH, —COOH and (C₁₋₄)alkyloptionally substituted with

and wherein the (C₁₋₄)alkyl portion of said —NH(C₁₋₄)alkyl is optionallysubstituted with

-   -   -   d) —C(═O)N(R⁹⁵)R⁹⁶, wherein R⁹⁵ is H and R⁹⁶ is selected            from cyclopropyl, —SO₂—R⁹⁶′ and —(C₁₋₄)alkyl-R⁹⁶², wherein            -   R⁹⁶¹ is CH₃, CH₂CH₃, phenyl, cyclopropyl, or —N(CH₃)₂;                and            -   R⁹⁶² is phenyl, —COOH, —N(CH₃)₂, or Het; wherein Het is                selected from

and wherein said phenyl is optionally substituted with —N(CH₃)₂ and saidHet is optionally substituted with oxo; or R⁹⁵ and R⁹⁶, together withthe N to which they are attached, are linked together to form a6-membered heterocycle which may be saturated or unsaturated and whichmay optionally contain one or two further heteroatoms each independentlyselected from N and O; said heterocycle being optionally substitutedwith —COOH; and

-   -   -   e) —O(C₁₋₄)alkyl optionally substituted with R⁹⁷ wherein R⁹⁷            is selected from —OH, —COOH, —C(═O)O—CH₂CH₂—NHCH₃,            —C(═O)N(R⁹⁷¹)R⁹⁷², —NH₂, —NH—(C₃₋₇)cycloalkyl,

and Het;

-   -   -   -   provided that the carbon atom of —O—(C₁₋₄)alkyl which is                directly bonded to 0 is not also directly bonded to —OH,                or —NH—(C₃₋₇)cycloalkyl;            -   wherein Het is selected from

and N and wherein said Het is optionally substituted with one or twosubstituents each independently selected from halo, oxo, CH₃ and —OH;and

-   -   -   -   wherein R⁹⁷¹ is H or CH₃ and R⁹⁷² is selected from H,                —OH, —NHC(═O)—CH₃, —NHC(═O)—NH₂, (C₁₋₄)alkyl,                cyclopropyl, phenyl and Het; wherein Het is selected                from

and

wherein said (C₁₋₄)alkyl is optionally substituted with —OH, —COOH,—N(CH₃)₂ or

provided that when R⁹⁷² is (C₁₋₄)alkyl, the carbon atom of (C₁₋₄)alkylwhich is directly bonded to N is not also directly bonded to —OH;

-   -   -   -   and wherein said cyclopropyl is optionally substituted                with —COOH, and wherein said phenyl is optionally                substituted with —OH, —COOH, or —CH═CH—COOH;            -   or R⁹⁷¹ and R⁹⁷², together with the N to which they are                attached, are linked together to form a 5- or 6-membered                heterocycle which may be saturated or unsaturated and                which may optionally contain one or two further                heteroatoms each independently selected from N and O;                said heterocycle being optionally substituted with CH₃                or —COOH.

Specific Embodiments

Included within the scope of this invention is each single compound offormula (I) as presented in Tables 1 to 7.

The compounds of formula (I) are effective inhibitors of wild type HIVas well as of the double mutation enzyme K103NNY181C. The compounds ofthe invention may also inhibit the single mutation enzymes V106A, Y188L,K103N, Y181C, P236L and G190A (among others). The compounds may alsoinhibit other double mutation enzymes including K103N/P225H, K103NN1081and K103N/L1001.

The compounds of formula (I) possess inhibitory activity against HIV-1replication. When administered in suitable dosage forms, they are usefulin the treatment of AIDS, ARC and related disorders associated withHIV-1 infection. Another aspect of the invention, therefore, is a methodfor treating HIV-1 infection which comprises administering to a humanbeing, infected by HIV-1, a therapeutically effective amount of acompound of formula (I), as described above. Whether it is termedtreatment or prophylaxis, the compounds may also be used to preventperinatal transmission of HIV-1 from mother to baby, by administrationto the mother before giving birth and to the child within the first daysof life.

The compounds of formula (I) may be administered in single or divideddoses by the oral, parenteral or topical routes. A suitable oral dosagefor a compound of formula (I) would be in the range of about 0.5 mg to 3g per day. A preferred oral dosage for a compound of formula (I) wouldbe in the range of about 100 mg to 800 mg per day for a patient weighing70 kg. In parenteral formulations, a suitable dosage unit may containfrom 0.1 to 250 mg of said compounds, preferably 1 mg to 200 mg, whereasfor topical administration, formulations containing 0.01 to 1% activeingredient are preferred. It should be understood, however, that thedosage administration from patient to patient would vary. The dosage forany particular patient will depend upon the clinician's judgment, whowill use as criteria for fixing a proper dosage the size and conditionof the patient as well as the patient's response to the drug.

When the compounds of the present invention are to be administered bythe oral route, they may be administered as medicaments in the form ofpharmaceutical preparations that contain them in association with acompatible pharmaceutical carrier material. Such carrier material can bean inert organic or inorganic carrier material suitable for oraladministration. Examples of such carrier materials are water, gelatin,talc, starch, magnesium stearate, gum arabic, vegetable oils,polyalkylene-glycols, petroleum jelly and the like.

The compounds of formula (I) can be used in combination with one or moreother antiretroviral drug known to one skilled in the art, as a combinedpreparation useful for simultaneous, separate or sequentialadministration for treating or preventing HIV infection in anindividual. Examples of antiretroviral drugs, including approved andinvestigational drugs, that may be used in combination therapy withcompounds of formula (I) include but are not limited to:

-   -   NRTIs (nucleoside or nucleotide reverse transcriptase        inhibitors; including but not limited to zidovudine, didanosine,        zalcitabine, stavudine, lamivudine, emtricitabine, abacavir, and        tenofovir);    -   NNRTIs (non-nucleoside reverse transcriptase inhibitors;        including but not limited to nevirapine, delavirdine, efavirenz,        capravirine, etravirine, rilpivirine, GW695634 and BILR 355);    -   protease inhibitors (including but not limited to ritonavir,        tipranavir, saquinavir, nelfinavir, indinavir, amprenavir,        fosamprenavir, atazanavir, lopinavir, VX-385 and TMC-114);    -   entry inhibitors including but not limited to CCR5 antagonists        (including but not limited to maraviroc (UK-427,857), SCH417690,        GW873140 and TAK-652), CXCR4 antagonists (including but not        limited to AMD-11070), fusion inhibitors (including but not        limited to enfuvirtide (T-20)) and others (including but not        limited to PRO-542 and BMS488043);    -   integrase inhibitors (including but not limited to c-1605,        BMS-538158 and JTK-303);    -   TAT inhibitors;    -   maturation inhibitors (including but not limited to PA457);    -   immunomodulating agents (including but not limited to        levamisole); and    -   antifungal or antibacterial agents (including but not limited to        fluconazole). Moreover, a compound of formula (I) can be used        with at least one other compound of formula (I).

The pharmaceutical preparations can be prepared in a conventional mannerand finished dosage forms can be solid dosage forms, for example,tablets, dragees, capsules, and the like, or liquid dosage forms, forexample solutions, suspensions, emulsions and the like. Thepharmaceutical preparations may be subjected to conventionalpharmaceutical operations such as sterilization. Further, thepharmaceutical preparations may contain conventional adjuvants such aspreservatives, stabilizers, emulsifiers, flavor-improvers, wettingagents, buffers, salts for varying the osmotic pressure and the like.Solid carrier material which can be used include, for example, starch,lactose, mannitol, methyl cellulose, microcrystalline cellulose, talc,silica, dibasic calcium phosphate, and high molecular weight polymers(such as polyethylene glycol).

For parenteral use, a compound of formula (I) can be administered in anaqueous or non-aqueous solution, suspension or emulsion in apharmaceutically acceptable oil or a mixture of liquids, which maycontain bacteriostatic agents, antioxidants, preservatives, buffers orother solutes to render the solution isotonic with the blood, thickeningagents, suspending agents or other pharmaceutically acceptableadditives. Additives of this type include but are not limited to, forexample, tartrate, citrate and acetate buffers, ethanol, propyleneglycol, polyethylene glycol, complex formers (such as EDTA),antioxidants (such as sodium bisulfite, sodium metabisulfite, andascorbic acid), high molecular weight polymers (such as liquidpolyethylene oxides) for viscosity regulation and polyethylenederivatives of sorbitol anhydrides. Preservatives may also be added ifnecessary, such as benzoic acid, methyl or propyl paraben, benzalkoniumchloride and other quaternary ammonium compounds.

The compounds of this invention may also be administered as solutionsfor nasal application and may contain in addition to the compounds ofthis invention suitable buffers, tonicity adjusters, microbialpreservatives, antioxidants and viscosity-increasing agents in anaqueous vehicle. Examples of agents used to increase viscosity arepolyvinyl alcohol, cellulose derivatives, polyvinylpyrrolidone,polysorbates or glycerin. Microbial preservatives added may includebenzalkonium chloride, thimerosal, chloro-butanol or phenylethylalcohol.

Additionally, the compounds provided by the invention may beadministerable by suppository.

Methodology and Synthesis

In general, the compounds of formula (I) are prepared by known methodsfrom readily available starting materials, using reaction conditionsknown to be suitable for the reactants. Schemes 1-7 illustrate thegeneral methods used to prepare the compounds of formula (I).

General methods for preparing a compound of formula (I), wherein Y ishalo (e.g. Cl, Br or I), P is a protecting group, R¹, R², R³, R⁴, R⁵,R⁶, R⁷, Ar, and X are as defined herein and R^(4a) is a precursor of R⁴(or identical to R⁴), are described in Scheme 1.

Briefly, thiol or alcohol 1(i) can be alkylated with an α-haloaceticacid ester in the presence of a base to give 1(ii), which can betransformed to acid 1(iii) after hydrolysis of the ester protectinggroup. Alternatively, 1(iii) can be obtained directly by alkylation withα-haloacetic acid. The reaction of acid 1(iii) with aniline 1(iv) canprovide the amide 1(v) using the standard methods for preparing amides.Alternatively, amide 1(v) can also be obtained by the alkylation of 1(i)with 1(vi), which is readily available from aniline 1(iv) andα-haloacetyl chloride or bromide. Finally, amide 1(v) can be readilytransformed to a compound of formula (I), if R^(4a) is different fromR⁴, using methods known to the skilled in the art. For example, whenR^(4a) is —OH, or a protected form thereof, the group R^(4a) may betransformed to an —OCH₂COOH group by alkylation with an α-haloaceticester fragment, followed by deprotection of the ester, to give compound1(vi). Coupling of the acid with amines of the formula HN(R⁵)R⁶, usingmethods well known in the art, provide compounds of general formula 1(vii). Alternatively, when R^(4a) is —COOH or a protected form thereof,the group R^(4a) may be transformed to a group of formula —CON(R⁵)R⁶ bycoupling with amines of the formula HN(R⁵)R⁶, using methods well knownin the art, to provide compounds of general formula 1(viii).Furthermore, when R^(4a) is —NH₂, or a protected form thereof, the groupR^(4a) may be transformed to a group of formula —NH(C═O)R⁷ by well knownacylation procedures, to give compounds of general formula 1(ix). Inaddition, protecting group removal, alkylation, coupling, amideformation or functional group modifications are contemplated, to carryout other transformations of compound 1(v) to other compounds of formula(I).

Anilines such as 1(iv) are either commercially available or can beprepared by known methods. General methods for preparing substitutedanilines 2(ii) and 2(iii), wherein Y is halo (e.g. Br or I), R², R³, R⁹,R⁴¹ and R⁴² are as defined herein and R^(9a) and R^(41a) are precursorsof (or identical to) R⁹ and R⁴¹, respectively, are described in Scheme2.

Briefly, 4-bromo or 4-iodoaniline 2(i) can be readily transformed toanilines 2(ii) or 2(iii) using the typical conditions of the Sonogashirareaction or the Suzuki coupling.

The preparation of compounds of formula (I) wherein Ar is tetrazole,1,2,4-triazole, imidazole or 1,2,3-triazole and R¹¹, R¹², R¹³, R¹⁴, R¹⁵and R^(Ar) are as defined herein is described in Scheme 3.

The key isocyanates 3(ii) are commercially available or can be easilyprepared by known methods from aniline 3(i). Tetrazole 3(iii) can beprepared by reacting isocyanate 3(ii) with sodium azide. Triazole 3(iv)can be obtained from the condensation of isocyanate 3(ii) withacylhydrazide followed by treatment with base or acid. Imidazole 3(v)can be obtained from 3(ii) by treatment with1-amino-2,2-ethylenedioxypropane. Triazole 3(vi) can be prepared byreacting the lithium salt of trimethylsilyldiazomethane with 3(ii)followed by the alkylation with tert-butyl bromoacetate and potassiumhydroxide treatment. Finally, the compounds of formula (I) can beobtained from 3(iii), 3(iv), 3(v) and 3(vi) using the additional stepsdescribed in Scheme 1.

The preparation of compounds of formula (I) wherein Ar is thiazole orthiadiazole, P is a protecting group and R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ areas defined herein is described in Scheme 4.

The reaction of bromomethylketone 4(i) with benzotriazole followed withthe treatment with p-toluenesulfonyl hydrazide gives intermediate 4(ii).The thiadiazole 4(iii) can be prepared from 4(ii) by treatment withthionyl chloride. The treatment of 4(iii) with thioglycolate gives 4(iv)and finally a compound of formula (I) using the sequence described inScheme 1. The bromomethylketone 4(i) can also be transformed to sulfide4(v) by reaction with thioglycolate in the presence of a base. Thebromination of 4(v) followed by the treatment with thioformamide gives4(vi) that can easily be transformed to a compound of formula (I) usingthe sequence described in Scheme 1.

The preparation of compounds of formula (I) wherein Ar is pyrazole, P isa protecting group, and R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ are as defined hereinis described in Schemes 5-7.

Pyrazole 5(ii) can be easily obtained by reacting hydrazine 5(i) withmethyl 3,3-dimethoxypropionate. Hydroxypyrazole 5(ii) can be transformedto the corresponding thiol derivative 5(iii) with the Lawesson reagent.Finally, pyrazole derivatives 5(ii) and 5(iii) can be converted tocompounds of formula (I) by using the sequence described in Scheme 1.

The pyrazole derivatives 6(iv) and 6(vi) can be obtained starting withphenylacetate 6(i). The reaction of 6(i) with the appropriateelectrophile, tert-butoxybis(dimethylamino)methane or acetic anhydride,can give intermediates 6(ii) and 6(v), which can be easily transformedto pyrazoles 6(iii) and 6(vi) respectively upon treatment withhydrazine. The methyl ether derivative 6(iii) can be transformed to thecorresponding hydroxypyrazole 6(iv). Finally, using the steps describedin Scheme 1, 6(iv) and 6(vi) can be converted to compounds of formula(I).

Pyrazole 7(iii) can be obtained from the Claisen condensation ofacetophenone 7(i) with ethyl formate in the presence of a base such assodium methoxide to give 7(ii) followed by condensation with hydrazine.Pyrazole 7(iii) can be converted to the bromo derivative 7(iv) upontreatment with bromine. Pyrazole 7(iv) can be transformed to a mixtureof isomers (7(v) and isomer), which upon treatment with n-butyllitium inthe presence of (i-Pr₃Si—S)₂, followed by the reaction withtetrabutylammonium fluoride in the presence of x-haloacetic acid estercan be converted to 7(vi). Finally, using the sequence of stepsdescribed in Scheme 1, 7(vi) can be transformed to compounds of formula(I).

Processes and reactants for preparing compounds of formula 1 areillustrated further by the examples hereinafter.

EXAMPLES

The present invention is illustrated in further detail by the followingnon-limiting examples. All reactions were performed in a nitrogen orargon atmosphere unless otherwise stated. Room temperature is 18 to 22°C. (degrees Celsius). Solution percentages or ratios express a volume tovolume relationship, unless stated otherwise. Purification by reversephase HPLC (RP-HPLC) was performed using a gradient of MeCN/H₂Ocontaining TFA (0.06%) (CombiPrep ODS-AQ 50×20 mm, 5 μ, 120A).Analytical HPLC was carried out under standard conditions using aCombiscreen ODS-AQ C18 reverse phase column, YMC, 50×4.6 mm i.d., 5 μM,120 Å at 220 nM, elution with a linear gradient as described in thefollowing table (Solvent A is 0.06% TFA in H₂O; solvent B is 0.06% TFAin CH₃CN):

Time (min) Flow (mL/min) Solvent A (%) Solvent B (%) 0 3.0 95 5 0.5 3.095 5 6.0 3.0 50 50 10.5 3.5 0 100

Abbreviations or symbols used herein include:

-   Ac: acetyl;-   Boc: tert-butoxycarbonyl;-   Bu: butyl;-   tBu: 1,1-dimethylethyl (tert-butyl)-   tBuOH: tert-butanol;-   CHAPS: 3-{(3-cholamidopropyl)dimethylammonio}-1-propanesulfonate;-   DEAD: diethyl azodicarboxylate;-   DMF: N,N-dimethylformamide;-   DMSO: dimethylsulfoxide;-   dppf: 1,1′-bis(diphenylphosphino)ferrocene;-   DTT: DL-dithiothreitol;-   Et: ethyl;-   Et₂O: diethyl ether;-   EtOH: ethanol;-   EtOAc: ethyl acetate;-   GSH: glutathione;-   HPLC: high performance liquid chromatography;-   iPr: 1-methylethyl (isopropyl);-   LiHMDS: lithium hexamethyldisilazide;-   Me: methyl;-   MeOH: methanol;-   MeCN: acetonitrile;-   n-BuLi: n-butyllithium;-   NaHMDS: sodium hexamethyldisilazide;-   NMR: nuclear magnetic resonance;-   Ph: phenyl;-   Pr: propyl;-   RP-HPLC: reverse phase high performance liquid chromatography;-   TBAF: tetrabutylammonium fluoride;-   TFA: trifluoroacetic acid;-   THF: tetrahydrofuran;-   TLC: thin layer chromatography.    Syntheses

The following examples illustrate methods for preparing compounds of theinvention.

Example 1 (Entry 2015) (Bl 211361)

a) Compound 1.2

To a solution of N-[4-(tert-butyl)phenyl]acetamide 1.1 (2.00 g, 10.5mmol) in a mixture of acetic acid (3.0 mL) and 12 N HCl (4.6 mL) wasadded dropwise a solution of NaClO₃ (170 mg, 1.60 mmol) in water (1 mL).After 30 min the resulting orange suspension was diluted with water (80mL), the precipitate was filtered, washed with water and dried to givethe compound 1.2 (2.0 g, 84% yield) as an off-white solid.

b) Compound 1.3

A solution of N-[4-(tert-butyl)-2-chlorophenyl]acetamide 1.2 (2.00 g,8.86 mmol) in a mixture of 36 N H₂SO₄ (14 mL) and water (2.9 mL) washeated at 120° C. for 18 h. After cooling the reaction mixture waspoured over ice, aqueous NaOH solution (10 M) was added until the pH wasalkaline and the mixture was extracted with EtOAc. The organic phase waswashed with brine, dried (MgSO₄), filtered and concentrated underreduced pressure. The resulting oil 1.3 (767 mg, 40% yield) was used assuch in the next step.

c) Compound 1.4

To a solution of compound 1.3 (765 mg, 4.16 mmol) in CH₂Cl₂ (5 mL) wasadded di-2-pyridylthiocarbonate (966 mg, 4.16 mmol). The solution wasstirred at room temperature overnight. The reaction mixture was washedsuccessively with saturated aqueous NaHCO₃ solution and brine, dried(MgSO₄), filtered and concentrated under reduced pressure to givecompound 1.4 (930 mg, 99% yield).

d) Compound 1.5

To a solution of compound 1.4 (925 mg, 4.10 mmol) in EtOH (200 mL) wasadded NaN₃ (4.3 g, 66 mmol) and the mixture was heated to 70° C. After 2h the reaction mixture was cooled to room temperature and 12 N HCl (2mL) was added. The mixture was concentrated and diluted with EtOAc. Theorganic layer was extracted with aqueous 1 N NaOH solution. The aqueouslayer was acidified with aqueous 6 N HCl solution and a whiteprecipitate formed. The suspension was filtered and the resulting solidwas triturated with Et₂O/hexane (1/1) to give compound 1.5 (941 mg, 85%yield) as an off white solid.

e) Compound 1.6

To a solution of pyridine (0.34 mL, 4.20 mmol) and compound 1.5 (930 mg,3.46 mmol) in DMSO (25 mL) was added ethyl 2-bromoacetate (392 μL, 3.46mmol). The resulting light yellow solution was stirred at roomtemperature for 2 h. The reaction mixture was then diluted with EtOAcand was successively washed with water and brine, dried (MgSO₄),filtered and concentrated under reduced pressure. The crude ester wasdissolved in THF (30 mL) and MeOH (10 mL) and aqueous 1 N NaOH solution(3 mL, 3 mmol) was added. The solution was stirred at 55° C. for 60 min.The THF/MeOH was evaporated under reduced pressure and the residue wasdissolved in aqueous 1 N NaOH solution. The solution was slowlyacidified to pH 2 at 0° C. with aqueous 1 N HCl solution. The suspensionwas filtered and the resulting solid was rinsed with water and driedunder reduced pressure to give compound 1.6 (600 mg, 99% yield) as awhite solid.

f) Compound 1.7

A solution of 4-bromo-2-chloroaniline (4.00 g, 19.37 mmol),bis(pinacolato)diboron (5.90 g, 23.2 mmol) and KOAc (12.3 g, 58.1 mmol)in DMSO (100 mL) was deoxygenated by bubbling nitrogen through it for 45min. PdCl₂(dppf) (1.42 g, 1.94 mmol) and dppf (1.07 g, 1.94 mmol) werethen added and the mixture was heated at 100° C. for 4 h. After coolingto room temperature the reaction mixture was diluted with EtOAc, washedsuccessively with water and brine, dried (MgSO₄), filtered andconcentrated under reduced pressure. The crude product was purifiedtwice by flash chromatography using CH₂Cl₂ to give intermediate 1.7(2.15 g, 44% yield) as a white solid.

g) Compound 1.8

To a solution of methyl (4-bromophenyl)acetate (obtained from thecorresponding acid (267.5 mg, 1.2 mmol) upon treatment with excessdiazomethane) in 1,4-dioxane (5 mL) were added intermediate 1.7 (315 mg,1.20 mmol) and K₃PO₄ (792 mg, 3.73 mmol). After degassing the reactionmixture for 45 min, PdCl₂(dppf) (137 mg, 0.19 mmol) and dppf (136 mg,0.06 mmol) were added and the mixture was heated at 100° C. for 3 h.After cooling to room temperature the reaction mixture was diluted withEtOAc, washed successively with water and brine, dried (MgSO₄), filteredand concentrated under reduced pressure. The crude product was purifiedby flash chromatography using hexane/EtOAc (80/20) to give compound 1.8(164 mg, 48% yield)

h) Compound 2015

To an ice-cold solution of acid 1.6 (30.6 mg, 0.09 mmol) and aniline 1.8(25.8 mg, 0.09 mmol) in pyridine (3 mL) was added PCl₃ (8.3 μL). Themixture was stirred at 0° C. for 2 h, quenched with a few drops ofwater, and concentrated under reduced pressure. The crude product wasdissolved in EtOAc and the resulting solution was successively washedwith aqueous 10% citric acid solution, water and brine, dried (MgSO₄),filtered and concentrated under reduced pressure. The crude product waspurified by flash chromatography using hexane/EtOAc (75/25) to affordthe corresponding ester (20 mg, 37% yield) as a white solid.

To a solution of the ester (20 mg, 0.034 mmol) in THF (3 mL)/MeOH (1 mL)was added 1 N NaOH (70 μL, 0.070 mmol). After 1 h at 55° C., thereaction was concentrated and the crude acid was purified by RP-HPLC Thepure fractions were combined and concentrated to give compound 2015 (6.5mg, 33% yield) as a white solid. ¹H-NMR (DMSO-d₆): δ 12.35 (bs s, 1H);10.03 (s, 1H); 7.83-7.79 (m, 3H); 7.73-7.63 (m, 5H); 7.36-7.34 (m, 2H);4.47 (s, 2H); 3.62 (s, 2H); 1.36 (s, 9H).

Example 2 (Entry 2033) (Bl 211695)

a) Compound 2.1

To a solution of 4-iodo-2-chloroaniline (5.00 g, 19.7 mmol) in THF (40mL) was added dropwise NaHMDS (1 M in THF, 41.4 mL) and the mixture wasstirred at room temperature for 90 min. Boc₂O (4.10 g, 19.0 mmol) in THF(30 mL) was added to the reaction mixture and the resulting solution wasstirred overnight. The reaction mixture was diluted with water andextracted twice with EtOAc. The combined organic phase was successivelywashed with aqueous 1 N HCl, water and brine, dried (MgSO₄), filteredand concentrated under reduced pressure. The crude product was purifiedby flash chromatography using hexane/EtOAc (99/1 to 4:1) to givecompound 2.1 as a light yellow oil (5.5 g, 79% yield).

b) Compound 2.2

To a solution of cyclopropylbromide (6.97 mL, 87.0 mmol) in THF (90 mL)cooled to −78° C. was added nBuLi (2.5 M in hexane, 34 mL) over 45 min.After 1 h, a solution of ZnBr₂ (flame dried under high vacuum, 23.2 g,103 mmol) in THF (90 mL) was added by cannula and the mixture wasallowed to warm to room temperature. After 1 h a solution of compound2.1 dissolved in THF (90 mL) was added followed by Pd(PPh₃)₄ (2.15 g,1.86 mmol) under stream of nitrogen. The reaction mixture was thenheated at reflux for 1 h, cooled in an ice bath and quenched with amixture of aqueous 1 N HCl solution and aqueous 5% Na₂S₂O₃ solution. Theresulting mixture was extracted with Et₂O several times and the combinedorganic layers were successively washed with aqueous 1 N HCl solution,water and brine, dried (MgSO₄), filtered and concentrated under reducedpressure. The crude product was dissolved in hexane (100 mL) andfiltered through a silica gel pad. The filtrate was concentrated toyield compound 2.2 (6.74 g, 87% yield) as a clear oil.

c) Compound 2.3

A solution of compound 2.2 (1.27 g, 4.74 mmol) in anhydrous HCl indioxane (4 N, 20 mL) was heated at 45° C. for 30 min. The resultingsuspension was concentrated to dryness and the viscous oil waspartitioned between EtOAc and water. The aqueous layer was made alkalineusing aqueous 1 N NaOH solution, and extracted with EtOAc. The organicphase was washed with brine, dried (MgSO₄), filtered and concentratedunder reduced pressure to give aniline 2.3 (511.0 mg, 64% yield) as abeige oil.

d) Compound 2.4

Following the procedure described in Example 1, Steps c and d, compound2.4 was obtained in 53% yield.

e) Compound 2.5

Following the procedure described in Example 1 Step g, but using thecorresponding ethyl ester, aniline 2.5 was obtained as an orange solidin 35% yield.

f) Compound 2.6

To a mixture of aniline 2.5 (202 mg, 0.70 mmol) and Et₃N (110 μL, 0.79mmol) in CH₂Cl₂ (8 mL) was added bromoacetyl chloride (65 μL, 0.75mmol). After 18 h the reaction mixture was diluted with EtOAc, washedwith water and brine, dried (MgSO₄), filtered and concentrated underreduced pressure. The crude product was purified by flash chromatographyusing hexane/EtOAc (75/25) to give compound 2.6 (247 mg, 86% yield) as abrown solid.

g) Compound 2033

To a solution of compound 2.4 (39.0 mg, 0.15 mmol) in DMF (2 mL) wasadded compound 2.6 (62.0 mg, 0.15 mmol) and K₂CO₃ (25 mg, 0.18 mmol).After 2 h, aqueous 1 N NaOH solution (0.5 mL) was added and stirring wascontinued for 2 h. The reaction mixture was quenched with TFA (0.5 mL),The resulting crude acid was purified by HPLC using a gradient ofMeCN/H₂O containing TFA (0.06%) (CombiPrep ODS-AQ 50×20 mm, 5 μ, 120A).The pure fractions were combined and concentrated to give compound 2033(42 mg, 51% yield) as a white solid. ¹H-NMR (DMSO-d₆) δ 12.34 (br s,1H); 10.02 (s, 1H); 7.81 (d, J=8.6 Hz, 1H); 7.79, (d, 2.0 Hz, 1H);7.66-7.61 (m, 4H); 7.56 (d, J=2.2 Hz, 1H, 7.37-7.31 (m, 3H); 4.46 (s,2H); 3.61 (s, 2H); 2.14-2.05 (m, 1H); 1.11-1.05 (m, 2H); 0.89-0.84 (m,2H).

Example 3 General Procedure for the Chlorination of Anilines

A solution of 3-methyl-5-(trifluoromethyl)aniline (2.0 g, 11.4 mmol) andN-chlorosuccinimide (1.7 g, 12.7 mmol) in MeCN (15 mL) was heated for 6h. Upon cooling the reaction was concentrated to dryness and theresulting mixture was purified by flash chromatography usinghexane/EtOAc (95/5) to give compound 3.1 (587.8 mg, 25% yield) as aclear oil, followed by hexane/EtOAc (90/10) to obtain compound 3.2(611.9 mg, 26% yield) as a colorless oil.

Example 4 (Entry 4067) (Bl211905)

a) Compound 4.3

To a solution of aniline 4.1 (706.2 mg, 2.78 mmol) in THF (27 mL) wasadded cuprous iodide (55.8 mg, 0.29 mmol), Et₂NH (2.37 mL, 22.9 mmol)and compound 4.2 (370 mg, 2.93 mmol). The mixture was degassed for 15min by bubbling argon through the solution. Pd(PPh₃)₄ (339 mg, 0.29mmol) was added and the reaction mixture was heated at reflux untiltotal disappearance of the starting material as indicated by TLC. Theblack solution was cooled to room temperature, silica gel was added andall volatiles were removed under reduced pressure to give a dry powderwhich was applied at the top of a column. The crude compound waspurified by flash chromatography (hexane/EtOAc, 75/25) to affordcompound 4.3 (600 mg, 86% yield) as a brown oil.

b) Compound 4.4

LiAlH₄ (33.2 mg, 0.87 mmol) was added to an ice-cold THF/Et₂O (1:2)solution of compound 4.3. The reaction mixture was stirred at roomtemperature for 1 h then was poured over aqueous 1 N Rochelle salt/Et₂O(200 mL, 1:1). The organic phase was collected and the aqueous phase wasextracted with Et₂O (3×40 mL). The combined organic phases were washedwith brine (50 mL), dried (Na₂SO₄), filtered and concentrated underreduced pressure to afford the alcohol 4.4 (77.0 mg, 79% yield) as acolorless oil which was used as such in the following step.

c) Compound 4067

Oxalyl chloride (40 μL, 45 μmol) and DMF (one drop) were successivelyadded to an ice-cold solution of acid 4.5 (prepared from compound 2.4using a procedure analogous to that described in Example 1 step e) (135mg, 0.41 mmol) in CH₂Cl₂ (4 mL). The reaction mixture was stirred atroom temperature for 1 h then was concentrated under reduced pressure.The residue was dissolved in THF (5 mL) and cooled to 0° C. A solutionof amine 4.4 (77.0 mg, 0.34 mmol) in THF (1 mL) and pyridine (70 μL,0.86 mmol) were successively added to the solution. The reaction mixturewas stirred at room temperature for 2 h, diluted with saturated aqueousNaHCO₃ solution and extracted with Et₂O (3×50 mL). The combined organicphases were washed with brine, dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The crude residue was purified by flashchromatography (hexane/EtOAc, 4/1) to afford the pure amide 4067 (60.0mg, 27% yield) as a colorless oil. ¹H-NMR (DMSO-d₆): δ 10.04 (s, 1H),7.81 (d, J=8.6 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.60 (d, J=1.8 Hz, 1H),7.54 (d, J=1.8 Hz, 1H), 7.37 (dd, J=4.1, 2 Hz, 1H), 7.35 (dd, J=4.1, 2Hz, 1H), 4.49 (s, 2H), 3.65 (broad s, 1H), 2.16-2.12 (m, 1H), 1.23 (s,6H), 1.15-1.11 (m, 2H), 0.93-0.89 (m, 2H).

Example 5 (Entry 4177) (Bl212190)

a) Compound 4177

To an ice-cold solution of alcohol 4067 (200 mg, 0.39 mmol) in CH₂Cl₂ (4mL) was added Dess-Martin periodinane (328 mg, 0.77 mmol). The reactionmixture was stirred at room temperature for 30 min then diluted withsaturated aqueous Na₂S₂O₃ solution (50 mL) and extracted with Et₂O (3×50mL). The combined organic phases were washed with brine, dried (Na₂SO₄),filtered and concentrated under reduced pressure. The crude oil wasdissolved in EtOH (5 mL) and added to a solution of glycine methyl ester(72.9 mg, 0.58 mmol) and acetic acid (0.2 mL) in EtOH (5 mL) at roomtemperature. NaCNBH₃ (36.5 mg, 0.58 mmol) was then added and theresulting suspension was stirred at room temperature for 1 h. Thereaction mixture was diluted with saturated aqueous NaHCO₃ solution (30mL) and extracted with Et₂O (3×30 mL). The combined organic phases werewashed with brine, dried (Na₂SO₄), filtered and concentrated underreduced pressure. The crude oil was dissolved in DMSO (4 mL), cooled to0° C. and aqueous 1 N LiOH solution (0.39 mL, 0.39 mmol) was added. Theresulting mixture was stirred at room temperature for 30 min, dilutedwith TFA (0.5 mL) and purified by RP-HPLC to afford, afterlyophilization, compound 4177 (38.0 mg, 14% yield) as a white solid.¹H-NMR (DMSO-d₆): δ 10.09 (s, 1H), 8.91 (broad s, 1H), 7.88 (d, J=8.6Hz, 1H), 7.67 (dd, J=4.5, 2.7 Hz, 2H), 7.60 (d, J=1.8 Hz, 1H), 7.45 (dd,J=8.4, 1.6 Hz, 1H), 7.37 (dd, J=8.4, 1.7 Hz, 1H), 4.50 (s, 2H), 4.01 (s,2H), 3.66 (broad s, 2H), 3.18 (s, 2H), 2.17-2.11 (m, 1H), 1.41 (s, 6H),1.16-1.11 (m, 2H), 0.93-0.89 (m, 2H)

Example 6 (Entry 4181) (Bl212194)

a) Compound 6.1

Dess-Martin periodinane (196 mg, 0.46 mmol) was added to an ice-coldsolution of compound 4067 (217 mg, 0.42 mmol) in CH₂Cl₂ (4 mL). Theresulting mixture was stirred at room temperature for 1 h, diluted withsaturated aqueous Na₂S₂O₃ solution and extracted with Et₂O (3×30 mL).The combined organic phases were washed with brine, dried (Na₂SO₄),filtered and concentrated under reduced pressure. The crude oil wasdissolved in dry THF (2 mL) and transferred into an ice-cold solution ofpotassium tert-butoxide (182 mg, 1.62 mmol) and(methoxymethyl)triphenylphosphonium chloride (579 mg, 1.69 mmol) in THF(5 mL), which was previously stirred for 30 min. The resulting reactionmixture was stirred for 1 h at 0° C. then for 1 h at room temperature.Saturated aqueous NaHCO₃ solution (20 mL) was added and the mixture wasextracted with Et₂O (3×30 mL). The combined organic phases were washedwith brine, dried (Na₂SO₄), filtered and concentrated under reducedpressure. Purification by flash chromatography using hexane/EtOAc (7/3)afforded compound 6.1 (80.0 mg, 35% yield) as a colorless oil.

b) Compound 4181

Aqueous 10% HCl solution (3 mL) was added to an ice-cold solution ofcompound 6.1 (79.7 mg, 0.15 mmol) in THF (2 mL). The reaction mixturewas stirred for 30 min at 0° C., for 3 h at room temperature thenextracted with Et₂O (3×30 mL). The combined organic phases were washedwith saturated aqueous NaHCO₃ solution, brine, dried (Na₂SO₄), filteredand concentrated under reduced pressure. The crude oil was dissolved intBuOH/CH₂Cl₂ (3 mL, 3:1). Aqueous pH 7.0 potassium phosphate buffer (3mL) was added, followed by 2-methyl-2-butene (5 mL) and NaClO₂ (66.5 mg,0.74 mmol). The reaction mixture was stirred for 3 h at roomtemperature, diluted with aqueous 10% HCl solution (10 mL) and extractedwith CH₂Cl₂ (5×10 mL). The combined organic phases were dried (Na₂SO₄),filtered and concentrated under reduced pressure. The crude product waspurified by RP-HPLC to afford, after lyophilization, compound 4181 (44.0mg, 55% yield) as a white solid. ¹H-NMR (DMSO-d₆) δ 12.1 (s, 1H), 9.94(s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.50 (d, J=1.5Hz, 1H), 7.38 (d, J=1.7 Hz, 1H), 7.28-7.21 m, 2H), 7.23 (dd, 1H), 4.38(s, 2H), 2.06-2.01 (m, 1H), 1.30 (s, 6H), 1.05-1.01 (m, 2H), 0.83-0.80(m, 2H).

Example 7 (Entry 4012) (Bl211683)

a) Compound 7.1

To a solution of aniline 4.1 (500 mg, 1.97 mmol) was added propargylbromide (258 μL, 2.17 mmol), cuprous iodide (37.5 mg, 197 μmol) andpyrrolidine (0.82 mL, 9.82 mmol). The mixture was degassed by bubblingargon in the solution for 20 min. Pd(PPh₃)₄ (228 mg, 0.20 mmol) wasadded and the mixture was heated at reflux for 5 h. The reaction mixturewas cooled to room temperature, silica gel was added and the volatileswere removed under reduced pressure to afford a dry powder. The crudecompound was purified by flash chromatography using hexane/EtOAC/Et₃N(50/45/5) to afford compound 7.1 (281 mg, 61% yield) as a brown oil.

b) Compound 4012

Using a method similar to the one described in Example 1, Step h, butusing aniline 7.1 in place of aniline 1.8, compound 4012 was obtained asa colorless oil (42% yield). ¹H-NMR (DMSO-d₆): 10.03 (s, 1H), 7.82-7.78(m, 2H), 7.72-7.66 (m, 2H), 7.57 (s, 2H), 7.39 (d, J=7.5 Hz, 1H), 4.46(s, 2H), 3.60 (s, 2H), 2.51 (s, 4H), 1.72 (s, 4H), 1.36 (s, 9H).

Example 8 (Entries 4069, 4072, 4130) (Bl211910, Bl211934, Bl212088)

a) Compound 8.1

Using a method similar to the one described in Example 4, Step a, butreplacing alkyne 4.2 with 3-amino-3-methyl-1-butyne, compound 8.1 wasobtained as a brown oil (98% yield).

b) Compound 8.2

Boc₂O (7.29 g, 33.4 mmol) was added to a solution of the propargylamine8.1 (6.97 g, 33.4 mmol) in MeOH (100 mL) at room temperature. Theresulting mixture was stirred at room temperature for 2 h, diluted withsaturated aqueous NaHCO₃ solution (100 mL) and extracted with EtOAc(3×50 mL). The combined organic phases were washed with saturatedaqueous NaHCO₃ solution and brine, dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The crude residue was purified byflash chromatography (hexane/EtOAc, 7/3) to afford the aniline 8.2 (5.64g, 55% yield) as a colorless oil.

c) Compound 4069

Using a method similar to the one described in Example 4, Step c,aniline 8.2 (497 mg, 1.61 mmol) yielded compound 4069 (717 mg, 74%yield) as an off white solid.

¹H-NMR (DMSO-d₆): δ 10.04 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.65 (d,J=8.3 Hz, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.47 (d, J=1.8 Hz, 1H), 7.34 (dd,J=8.2, 1.8 Hz, 1H), 7.32 (dd, J=8.5, 1.7 Hz, 1H), 7.13 (broad s 1H),4.46 (s, 2H), 2.13-2.07 (m, 1H), 1.52 (s, 6H), 1.41 (s, 9H), 1.11-1.09(m, 2H), 0.90-0.86 (m, 2H).

d) Compound 4072

Anhydrous 4 N HCl in 1,4-dioxane (0.23 mL, 0.93 mmol) was added at roomtemperature to a solution of compound 4069 (56.0 mg, 93 μmol) in1,4-dioxane (0.5 mL). The reaction mixture was stirred at roomtemperature overnight then concentrated under reduced pressure. Thecrude residue was purified by RP-HPLC to afford, after lyophilization,compound 4072 (33 mg, 70% yield) as a white solid.

¹H-NMR (DMSO-d₆): δ 10.08 (s, 1H), 8.52 (broad s, 3H), 7.91 (d, J=8.4Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.61 (d, J=5.6 Hz, 1H), 7.56 (d, J=1.86Hz, 1H), 7.43 (dd, J=8.4, 1.6 Hz, 1H), 7.33 (dd, J=8.4, 2.0 Hz, 1H),4.47 (s, 2H), 2.12-2.07 (m, 1H), 1.62 (s, 6H), 1.12-1.07 (m, 2H),0.89-0.85 (m, 2H).

e) Compound 4130

Acetic acid (30 μL) was added to a solution of aniline 4071 in EtOH (2mL) at room temperature. Salicylaldehyde (18.3 mg, 0.15 mmol) was thenadded, followed by NaCNBH₃ (5 μg, 75 μmol). The reaction was stirred atroom temperature for 1 h then concentrated under reduced pressure. Thecrude residue was purified by RP-HPLC to afford, after lyophilization,compound 4130 (18.8 mg, 62% yield) as a white solid.

¹H-NMR (DMSO-d₆): δ 10.26 (s, 1H), 10.14 (s, 1H), 9.17 (broad s, 2H),7.95 (d, J=8.4 Hz, 1H), 7.75 (d, J=1.8 Hz, 1H), 7.67 (d, J=8.2 Hz, 1H),7.60 (d, J=1.8 Hz, 1H), 7.54 (dd, J=8.6, 1.8 Hz, 1H), 7.40 (d, J=7.6 Hz,1H), 7.38 (dd, J=8.4, 1.7 Hz, 1H), 7.31 (dt, J=8.2, 1.3 Hz, 1H), 6.97(d, J=8.1 Hz, 1H), 6.91 (t, J=7.2 Hz, 1H), 4.51 (s, 2H), 4.33 (s, 2H),2.17-2.11 (m, 1H), 1.76 (s, 6H), 1.16-1.11 (m, 2H), 0.93-0.89 (m, 2H).

Example 9 (Entry 4062) (Bl211874)

a) Compound 9.2

Cyclobutanone (1.00 g, 14.3 mmol) was added to a −78° C. solution ofethynyl magnesium bromide (0.5M in THF, 40 mL, 20 mmol). The reactionmixture was stirred at room temperature for 1 h, diluted with saturatedaqueous NH₄Cl solution and extracted with Et₂O (4×30 mL). The combinedorganic phases were washed with brine, dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The crude oil was dissolved in THF(25 mL) and 2-chloro-4-iodoaniline (1.25 g, 4.93 mmol) was added,followed by cuprous iodide (94 mg, 190 mmol) and Et₂NH (1.3 mL, 12mmol). The mixture was degassed by bubbling argon through the solutionfor 15 min and Pd(PPh₃)₄ (570 mg, 0.49 mmol) was added. The solution washeated at reflux for 5 h. After cooling to room temperature, silica gelwas added and the volatiles were removed under reduced pressure to givea dry brown powder. The crude product was purified by flashchromatography (hexane/EtOAc, 19/1) to afford compound 9.2 (269 mg, 25%yield) as a brown oil.

b) Compound 4062

Using a method similar to the one described in Example 7, Step b,aniline 9.2 (61 mg, 0.28 mmol) gave compound 4062 (10.0 mg, 6% yield) asan off white solid. ¹H-NMR (CDCl₃): δ 9.39 (s, 1H), 8.31 (d, J=8.6 Hz,1H), 7.61 (d, J=1.8 Hz, 1H), 7.49-7.47 (m, 2H), 7.36-7.31 (m, 2H), 4.16(s, 2H), 2.55-2.50 (m, 2H), 2.36-2.30 (m, 2H), 2.23 (s, 1H), 1.91-1.83(m, 2H), 1.38 (s, 9H).

Example 10 (Entries 4098,4082) (Bl212033, Bl211987)

a) Compound 10.2

LiAlH₄ (446 mg, 11.7 mmol) was added to an ice-cold solution of compound10.1 (2.00 g, 11.8 mmol) in Et₂O (100 mL). The reaction mixture wasstirred at room temperature for 1 h then poured over aqueous 1 NRochelle salt solution (200 mL). The solution was diluted with Et₂O (200mL) and stirred vigourously for 1 h. The organic phase was collected,washed with brine, dried (Na₂SO₄), filtered and concentrated underreduced pressure. The crude oil was purified by flash chromatography(hexane/EtOAc, 4/1) to afford alcohol 10.2 (963 mg, 64% yield) as acolorless oil.

-   -   b) Compound 10.3

Using a method similar to the one described in Example 7, Step a,compound 10.2 (400 mg, 2.12 mmol) and 2-chloro-4-iodoaniline (791 mg,3.12 mmol) gave alcohol 10.3 (585 mg, 74% yield) as a brown oil.

c) Compound 4098

Using a method similar to the one described in Example 4, Step c,aniline 10.3 (131 mg, 0.52 mmol) gave compound 4098 (160 mg, 57% yield)as an off white solid. ¹H-NMR (DMSO-d₆): δ 10.04 (s, 1H), 7.83 (d, J=8.6Hz, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.57 (dd, J=7.2, 1.7 Hz, 2H), 7.39 (dd,J=8.4, 2.0 Hz, 1H), 7.33 (dd, J=8.4, 1.7 Hz, 1H), 4.58 (t, J=5.9 Hz,1H), 4.46 (s, 2H), 3.58-3.49 (m, 4H), 2.12-2.07 (m, 1H), 1.48 (s, 6H),1.12-1.07 (m, 2H), 0.89-0.85 (m, 2H).

d) Compound 4082

MsCl (1.2 μL, 15 μmol) was added to an ice cold solution of alcohol 4098(7.8 mg, 14 μmol) and Et₃N (4 μL, 28 μmol) in CH₂Cl₂ (1 mL). The mixturewas stirred at room temperature for 2 h, diluted with saturated aqueousNaHCO₃ solution (20 mL) and extracted with Et₂O (3×30 mL). The combinedorganic phases were washed with brine, dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The crude mesylate was dissolved inTHF (5 mL) and pyrrolidine (0.1 mL) was added. The mixture was heated atreflux overnight, cooled to 0° C., concentrated under reduced pressureand purified by RP-HPLC to afford, after lyophilization, compound 4082(3.7 mg, 44% yield). ¹H-NMR (DMSO-d₆): 610.04 (s, 1H), 9.37 (broad s,1H), 7.85 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.62 (s, 1H), 7.56(d, J=1.8 Hz, 1H), 7.41 (dd, J=8.6, 1.8 Hz, 1H), 7.33 (dd, J=8.2, 1.7Hz, 1H), 4.46 (s, 2H), 3.85-3.83 (m, 2H), 3.56-3.52 (m, 2H), 3.11-3.07(m, 2H), 2.12-2.08 (m, 1H), 2.04-1.98 (m, 1H), 1.90-1.86 (m, 2H), 1.54(s, 6H), 1.12-1.07 (m, 2H), 0.89-0.85 (m, 2H).

Example 11 (Entry 4167) (Bl212174)

a) Compound 11.1

DEAD (424 mg, 2.43 mmol) was added to an ice-cold solution) solution ofalcohol 10.2 (from Example 10) (240 mg, 1.87 mmol), 4-hydroxypyridine(196 mg, 2.06 mmol) and PPh₃ (638 mg, 2.43 mmol) in THF (20 mL). Thereaction mixture was stirred for 1 h at room temperature. Silica gel wasadded and the volatiles were removed under reduced pressure to afford adry powder which was applied on a pad of silica. Quick elution(hexane/EtOAc, 1/1) afforded alkyne 11.1 which was used as such in thefollowing step.

b) Compound 11.2

Using a method similar to the one described in Example 7, Step a,compound 11.1 (88.0 mg, 0.43 mmol) and 2-chloro-4-iodoaniline (108.7 mg,0.429 mmol) gave compound 11.2 (32.0 mg, 23% yield) as a brown oil.

c) Compound 4167

Using a method similar to the one described in Example 4, Step c,aniline 11.2 (32 mg, 97 μmol) yielded compound 4167 (24 mg, 40% yield)as an off white solid. ¹H-NMR (DMSO-d₆): δ 9.99 (s, 1H), 8.65 (d, J=7.0Hz, 2H), 7.78 (d, J=8.4 Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.51-7.47 (m,4H), 7.31 (dd, J=8.4, 1.7 Hz, 1H), 7.27 (dd, J=8.3, 1.8 Hz, 1H),4.46-4.45 (m, 2H), 4.40 (s, 2H), 3.91-3.89 (m, 2H), 2.05-2.00 (m, 1H),1.44 (s, 6H), 1.05-1.00 (m, 2H), 0.83-0.79 (m, 2H).

Example 12 (Entries 4083,4084) (Bl21989, Bl211999)

a) Compound 12.2

A solution of diethyl ester 12.1 (2.00 g, 10.7 mmol) in THF (15 mL) wasslowly added to an ice-cold suspension of LiAlH₄ (1.35 g, 35.4 mmol) inTHF (100 mL). The mixture was stirred at room temperature for 1 h thenNa₂SO₄.6H₂O was added until no more gas was formed. The reaction mixturewas filtered through Celite and concentrated under reduced pressure. Thecrude diol was dissolved in THF (100 mL), cooled to 0° C. and NaH (258mg, 10.7 mmol) was added. The resulting suspension was stirred at roomtemperature for 1 h and tert-butyldiphenylsilyl chloride (2.95 g, 10.7mmol) was added. The reaction mixture was stirred at room temperaturefor 1 h, diluted with saturated aqueous NH₄Cl solution (100 mL) andextracted with CH₂Cl₂ (3×100 mL). The combined organic phases werewashed with brine, dried (Na₂SO₄), filtered and concentrated underreduced pressure. The crude residue was purified by flash chromatography(hexane/EtOAc, 4:1) to afford pure silylether 12.2 (1.2 g, 33% yield).

b) Compound 12.3

Dess-Martin periodinane (2.99 g, 7.05 mmol) was added to an ice-coldsolution of compound 12.2 (2.40 g, 7.05 mmol) in CH₂Cl₂ (50 mL). Thereaction mixture was stirred at room temperature for 1 h, diluted withsaturated aqueous Na₂S₂O₃ solution (20 mL) and saturated aqueous NaHCO₃solution (20 mL) then extracted with Et₂O (3×20 mL). The combinedorganic phases were washed with brine, dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The crude aldehyde was dissolved inCH₂Cl₂ (5 mL) and transferred into an ice-cold solution of PPh₃ (7.39 g,7.05 mmol) and CBr₄ (4.67 g, 14.1 mmol) in CH₂Cl₂ (20 mL) that waspreviously stirred for 1 h at room temperature The resulting reactionmixture was stirred for 10 min at 0° C. and silica gel was added. Thevolatiles were removed under reduced pressure to afford a dry powder.The crude compound was purified by flash chromatography (hexane tohexane/EtOAc, 98:2) to afford the geminal dibromoalkene. To a cold (−78°C.) solution of this intermediate in THF (15 mL) was added n-BuLisolution (2 M in hexane, 5.6 mL). The reaction mixture was stirred for1.5 h at −78° C., for 1 h at room temperature, then diluted with water(5 mL) and extracted with Et₂O (3×50 mL). The combined organic phaseswere washed with brine, dried (Na₂SO₄), filtered and concentrated underreduced pressure. The crude residue was purified by flash chromatography(100% hexane then 2% EtOAc/98% hexane) to afford the alkynyl-silylether, which was diluted in THF (10 mL) and treated with TBAF (1 M inTHF, 8.46 mL, 8.46 mmol). The reaction mixture was stirred for 15 min atroom temperature and concentrated under reduced pressure. The residuewas purified by flash chromatography (hexane/EtOAc, 4/1) to affordcompound 12.3 (240 mg, 35% yield, 4 steps).

c) Compound 12.4

Using a method similar to the one described in Example 7, Step a,compound 12.3 (240 mg, 2.50 mmol) and 2-chloro-4-iodoaniline (633 mg,2.50 mmol) gave aniline 12.4 (370 mg, 67% yield) as a brown oil.

d) Compound 4083

Using a method similar to the one described in Example 4, Step c,aniline 12.4 (36.0 mg, 0.16 mmol) yielded compound 4083 (10 mg, 12%yield) as an off white solid. ¹H-NMR (DMSO-d₆): δ 10.14 (s, 1H), 7.91(d, J=8.6 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.71 (d, J=1.7 Hz, 1H), 7.65(d, J=1.7 Hz, 1H), 7.49-7.47 (m, 2H), 4.59 (s, 2H), 3.57 (s, 2H),2.28-2.22 (m, 1H), 1.27-1.22 (m, 2H), 1.06-1.01 (m, 6H).

e) Compound 4084

Dess-Martin periodinane (16.9 mg, 40.0 μmol) was added to an ice-coldsolution of compound 4083 (32.0 mg, 40.0 μmol) in CH₂Cl₂ (5 mL). Thereaction mixture was stirred at room temperature for 1 h, diluted withsaturated aqueous Na₂S₂O₃ solution and extracted with Et₂O (3×20 mL).The combined organic phases were washed with brine, dried (Na₂SO₄),filtered and concentrated under reduced pressure. The crude oil wasdissolved in t-BuOH/CH₂Cl₂ (3 mL, 3:1). Aqueous pH 7.0 potassiumphosphate buffer (3 mL) was added, followed by 2-methyl-2-butene (5 mL)and NaClO₂ (18 mg, 0.2 mmol). The reaction mixture was stirred for 3 hat room temperature, diluted with aqueous 10% HCl solution (10 mL) andextracted with CH₂Cl₂ (5×10 mL). The combined organic phases were dried(Na₂SO₄), filtered and concentrated under reduced pressure. The crudeproduct was purified by RP-HPLC to afford, after lyophilization, theacid 4084 (2.1 mg, 10% yield) as a white solid. ¹H-NMR (DMSO-d₆): δ12.77 (s, 1H), 9,91 (s, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.54 (d, J=8.3 Hz,1H), 7.47 (d, J=1.8 Hz, 1H), 7.44 (d, J=1.8 Hz, 1H), 7.27 (dd, J=8.4,1.8 Hz, 1H), 7.24 (dd, J=8.4, 1.7 Hz, 1H), 4.36 (s, 2H), 2.04-1.98 (m,1H), 1.43-1.40 (m, 2H), 1.31-1.28 (m, 2H), 1.03-0.98 (m, 2H), 0.80-0.76(m, 2H).

Example 13 (Entry 4094) (Bl212026)

a) Compound 4094

Using a method analogous to the one described in Example 10, Step d,alcohol 4084 (26 mg, 0.05 mmol), afforded compound 4094 (13 mg, 43%yield) as a white solid. ¹H-NMR (DMSO-d₆): δ 9.95 (s, 1H), 9.22 (broads, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.49 (d, J=1.8Hz, 1H), 7.43-7.41 (m, 1H), 7.28-7.24 (m, 2H), 4.38 (s, 2H), 3.40 (s,2H), 3.30-2.94 (m, 8H), 2.72 (s, 3H), 2.05-2.00 (m, 1H), 1.05-1.00 (m,2H), 0.98 (s(br), 2H), 0.82-0.78 (m, 4H).

Example 14 (Entry 1002) (Bl 211469)

a) Compound 14.1

To a solution of 2-chloro-4-methylacetophenone (3.45 g, 20.4 mmol) in1,4-dioxane (20 mL) was added at room temperature a solution of Br₂(1.16 mL, 22.4 mmol) in 1,4-dioxane (50 mL) over a period of 1 h. Thereaction mixture was stirred at room temperature for 20 min. The1,4-dioxane was evaporated under reduced pressure and the residue wasdissolved in Et₂O (100 mL). The resulting solution was successivelywashed with aqueous saturated NaHCO₃, water, and brine, dried (MgSO₄),filtered and concentrated under reduced pressure. The crude product waspurified by flash chromatography (CH₂Cl₂:hexane, 7:3) to yield compound14.1 (3.7 g, 73% yield) as a yellow oil.

b) Compound 14.2

Methyl thioglycolate (379 μL, 4.24 mmol) was added to a solution ofcompound 14.1 (1.00 g, 4.04 mmol) and Et₃N (619 μL, 4.44 mmol) inCH₂Cl₂. The reaction mixture was stirred at room temperature for 1 h.The mixture was then diluted with CH₂Cl₂ (100 mL), washed successivelywith aqueous 0.1 N HCl solution, aqueous saturated NaHCO₃, water andbrine. The organic layer was dried (MgSO₄), filtered and concentratedunder reduced pressure. The crude product was purified by flashchromatography (CH₂Cl₂:(CH₃)₂CO, 95:5) to afford compound 14.2 (1.1 g,100% yield) as a pale yellow solid.

c) Compound 14.3

To a solution of compound 14.2 (1.07 g, 3.93 mmol) in AcOH (30 mL) wasadded at room temperature a solution of bromine (202 μL, 3.93 mmol) inAcOH (10 mL) over a period of 30 min. The reaction mixture was stirredat room temperature for 30 min and poured in ether (200 mL). The organicphase was successively washed with water, aqueous saturated NaHCO₃,water and brine, dried (MgSO₄), filtered and concentrated under reducedpressure. The crude product was purified by flash chromatography(CH₂Cl₂) to afford compound 14.3 (1.23 g, 89% yield) as a clear oil.

d) Compound 14.4

Thioformamide (521.3 mg, 8.53 mmol) was added to a solution of compound14.3 (300.0 mg, 853.1 μmol) in iPrOH (20 mL). The reaction mixture wasstirred at 60° C. for 1 h then was concentrated under reduced pressure.The residue was purified by flash chromatography (CH₂Cl₂:(CH₃)₂CO, 95:5)to afford compound 14.4 (207 mg, 78% yield) as a yellow oil.

e) Compound 14.5

Ester 14.4 (207 mg, 660.9 μmol) was dissolved in DMSO (6.0 mL) andaqueous 1 N NaOH (2.0 mL, 2.0 mmol) solution was added to the solution.The reaction mixture was stirred at room temperature for 1 h andacidified (pH=2) with TFA. The mixture was then diluted with EtOAc (100mL) and successively washed with water and brine, dried (MgSO₄),filtered and concentrated under vacuum to give compound 14.5 (194 mg,98% yield).

f) Compound 1002

PCl₃ (10.2 μL, 116 μmol) was added to an ice-cold solution of compound14.5 (35.0 mg, 116 μmol) and compound 2.5 (from Example 2) (35.4 mg,128. μmol) in pyridine (3.0 mL). The reaction mixture was stirred atroom temperature for 30 min. Water (few drops) was added and the mixturewas concentrated under reduced pressure. The crude ester was dissolvedin DMSO (3.0 mL) and aqueous 1 N NaOH (1.0 mL, 1.0 mmol) solution wasadded to the solution. The reaction mixture was stirred at roomtemperature for 1 h and acidified (pH=2) with TFA. The solution waspurified by RP-HPLC and the pure fractions were concentrated to givecompound 1002 (6.2 mg, 10% yield) as an orange solid. ¹H NMR (DMSO-d₆) δ12.27 (broad s, 1H), 9.65 (s, 1H), 9.22 (s, 1H), 7.83 (d, J=8.4 Hz, 1H),7.77 (d, J=1.6 Hz, 1H), 7.65-7.63 (m, 3H), 7.38-7.30 (m, 4H), 7.16 (d,J=7.7 Hz, 1H), 3.76 (s, 2H), 3.61 (s, 2H), 2,34 (s, 3H).

Example 15 (Entry 1003) (Bl 211531)

a) Compound 15.2

A mixture of compound 15.1 (400 mg, 2.07 mmol) and methyl3,3-dimethoxypropionate (323 μL, 2.28 mmol) in MeOH (5.0 mL) was stirredat 70° C. for 24 h. The reaction mixture was concentrated under reducedpressure and the residue purified by flash chromatography(CH₂Cl₂:(CH₃)₂CO, 95:5) to afford compound 15.2 (104 mg, 24% yield) as ayellow solid.

b) Compound 15.3

To a solution of compound 15.2 (39.4 mg, 188.8 μmol) and tert-butylbromoacetate (30.7 μL, 207.7 μmol) in DMF (3.0 mL) at room temperaturewas added potassium carbonate (39.1 mg, 283.3 μmol). The reactionmixture was stirred at room temperature for 16 h, then was diluted withEtOAc (50 mL) and successively washed with water and brine, dried(MgSO₄), filtered and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography (CH₂Cl₂:(CH₃)₂CO, 95:5) toafford compound 15.3 (21.4 mg, 35% yield) as a yellow oil.

c) Compound 1003

TFA (1.00 mL, 13.0 mmol) was added dropwise to a solution of compound15.3 (13.2 mg, 41.0 μmol) in CH₂Cl₂ (2.0 mL) at room temperature. Thereaction mixture was stirred for 16 h and then concentrated undervacuum. PCl₃ (10.2 μL, 116.7 μmol) was then added to an ice-coldsolution of the resulting acid and compound 2.5 (Example 2) (11.3 mg,41.0 μmol) in pyridine (3.0 mL). The reaction mixture was stirred atroom temperature for 30 min. Water (few drops) was added and the mixturewas concentrated under reduced pressure. The crude ester was dissolvedin DMSO (2.0 mL) and aqueous 1 N NaOH (1.0 mL, 1.0 mmol) solution wasadded to the solution. The reaction mixture was stirred at roomtemperature for 1 h and acidified (pH=2) with TFA. The solution waspurified by RP-HPLC and the pure fractions were concentrated to givecompound 1003 (7.6 mg, 36% yield) as an orange solid. ¹H NMR (DMSO-d₆) δ12.36 (broad s, 1H), 9.36 (s, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.79 (d,J=2.2 Hz, 1H), 7.66 (d, J=1.9 Hz, 1H), 7.63 (d, J=8.2 Hz, 2H), 7.52 (d,J=2.0 Hz, 1H), 7.50 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.2 Hz,2H), 7.31 (d, J=8.2 Hz, 1H), 4.88 (s, 2H), 3.60 (s, 2H), 2.39 (s, 3H).

Example 16 (Entry 1004) (Bl 211546)

a) Compound 16.1

A mixture of compound 15.2 (250 mg, 1.20 mmol) and Lawesson's reagent(485 mg, 1.20 mmol) in toluene (15 mL) was heated under reflux for 4 h.The reaction mixture was then concentrated under reduced pressure andthe residue purified by flash chromatography (CH₂Cl₂:(CH₃)₂CO, 95:5) toafford compound 16.1 (86 mg, 32% yield) as a yellow oil.

b) Compound 16.2

To a solution of 16.1 (86.1 mg, 383 μmol) in DMF,(5.0 mL) at 0° C. wasadded K₂CO₃ (105.9 mg, 766.3 μmol). After stirring for 30 min,tert-butyl bromoacetate (62.2 μL, 421 μmol) was added and the reactionmixture was stirred at 0° C. for 1 h and then allowed to warm to roomtemperature and stirred for 2 h. EtOAc (50 mL) was added and the mixturewas washed with water and brine, dried (MgSO₄), filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography (CH₂Cl₂:(CH₃)₂CO, 95:5) to afford compound 16.2 (64.0 mg,49% yield) as a colorless oil.

c) Compound 16.3

TFA (1.00 mL, 13.0 mmol) was added dropwise to a solution of compound16.2 (58.4 mg, 172.3 μmol) in CH₂Cl₂ (3.0 mL) at room temperature. Thereaction mixture was stirred for 16 h and then concentrated underreduced pressure to afford compound 16.3 (48.7 mg, 100% yield).

d) Compound 1004

PCl₃ (10.2 μL, 116.7 μmol) was added to an ice-cold solution of compound16.3 (29.0 mg, 102.6 μmol) and compound 2.5 (Example 2) (32.7 mg, 112.8μmol) in pyridine (3.0 mL). The reaction mixture was stirred at roomtemperature for 30 min. Water (few drops) was added and the mixture wasconcentrated under reduced pressure. The crude ester was dissolved inDMSO (3.0 mL) and aqueous 1 N NaOH (1.0 mL, 1.0 mmol) solution was addedto the solution. The reaction mixture was stirred at room temperaturefor 1 h and acidified (pH=2) with TFA. The solution was purified byRP-HPLC and the pure fractions were concentrated to give compound 1004(15.8 mg, 29% yield) as a white solid. ¹H NMR (DMSO-d₆) δ 12.37 (broads, 1H), 9.65 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H),7.73 (d, J=1.9 Hz, 1H), 7.65-7.62 (m, 3H), 7.50 (s, 1H), 7.38 (d, J=8.1Hz, 1H), 7.34 (d, J=8.3 Hz, 2H), 7.24 (dd, J=8.0, 1.0 Hz, 1H), 6.66 (d,J=1.7 Hz, 1H), 3.75 (s, 2H), 3.61 (s, 2H), 2.37 (s, 3H).

Example 17 (Entry 1005) (Bl 211584)

a) Compound 17.2

To a cold (−78° C.) solution of (trimethylsilyl)diazomethane (2.0 M inhexane) (6.53 mL, 13.07 mmol) in THF (50 mL) was added dropwise 2.5 Mn-BuLi in hexane (5.23 mL, 13.07 mmol). After 20 min, a solution ofcompound 17.1 (2.0 g, 10.89 mmol) in THF (15 mL) was added dropwise andthe reaction mixture was stirred at −78° C. for 1 h. tert-Butylbromoacetate (1.93 mL, 13.07 mmol) was then added and the mixture wasstirred at −78° C. for 30 min and then at 0° C. for another 30 min. Themixture was treated with ice-water (50 mL) and Et₂O (300 mL) was added.The mixture was washed with water and brine, dried (MgSO₄), filtered andconcentrated under reduced pressure. The crude product was purified byflash chromatography (CH₂Cl₂:(CH₃)₂CO, 95:5) to afford compound 17.2(3.7 g, 83% yield) as a yellow oil.

b) Compound 17.3

A mixture of compound 17.2 (1.0 g, 2.43 mmol) and aqueous 10% KOHsolution (12.5 mL) in MeOH (25 mL) was heated under reflux for 2 h. TheMeOH was removed under reduced pressure and the mixture was neutralizedwith aqueous 1 N HCl solution. The aqueous phase was then extracted withEt₂O (2×10 mL). The combined organic extracts were washed with brine,dried (MgSO₄), filtered and concentrated under reduced pressure to givecompound 17.3 (683 mg, 99% yield) as a yellow solid.

c) Compound 1005

Using a method similar to the one described for Example 16, Step d,compound 17.3 (50.0 mg, 176.2 mmol) gave compound 1005 (42.7 mg, 46%yield) as a white solid. ¹H NMR (DMSO-d₆) δ 12.36 (broad s, 1H), 9.75(s, 1H), 8.06 (s, 1H), 7.79-7.77 (m, 2H), 7.65-7.61 (m, 4H), 7.50 (d,J=8.0 Hz, 1H), 7.36-7.32 (m, 3H), 3.87 (s, 2H), 3.61 (s, 2H), 2.41 (s,3H).

Example 18 (Entry 1007) (Bl 211689)

a) Compound 18.1

A mixture of compound 14.1 (Example 14) (1.00 g, 4.04 mmol),benzotriazole (529.4 mg, 4.44 mmol) and K₂CO₃ (558 mg, 4.04 mmol) intoluene (100 mL) was heated at reflux for 16 h. The cooled reactionmixture was washed with water and brine, dried (MgSO₄), filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography (CH₂Cl₂:(CH₃)₂CO, 97:3) to afford compound 18.1 (781 mg,68% yield) as a yellow oil.

b) Compound 18.2

A solution of compound 18.1 (781 mg, 2.73 mmol) and p-toluenesulfonylhydrazide (509 mg, 2.73 mmol) in benzene (25.0 mL) was heated at refluxfor 24 h. The mixture was cooled and concentrated under reduced pressureto give compound 18.2 (1.20 g, 97% yield) as a beige solid.

c) Compound 18.3

A solution of compound 18.2 (1.20 g, 2.65 mmol) in SOCl₂ (25 mL) wasstirred at 60° C. for 8 h. The reaction mixture was then concentratedunder reduced pressure and the residue purified by flash chromatography(CH₂Cl₂) to afford compound 18.3 (480 mg, 55% yield) as a yellow solid.

d) Compound 18.4

NaH (60% in oil) (33.5 mg, 838 pmol) was added to a solution of compound18.3 (229 mg, 698 μmol) and methylthioglycolate (74.9 μL, 838 μmol) inDMF (7 mL) at room temperature. The reaction mixture was stirred for 2h, quenched with aqueous 0.1 N HCl solution (2 mL) and then diluted withEtOAc (50 mL). The solution was successively washed with water andbrine, dried (MgSO₄), filtered and concentrated under reduced pressure.The residue was purified by flash chromatography (hexane:EtOAc, 8:2) toafford compound 18.4 (162 mg, 74% yield) as a yellow oil.

e) Compound 18.5

Aqueous 1.0 N NaOH solution (800 μL, 800 μmol) was added to a solutionof compound 18.4 (162 mg, 514 μmol) in DMF (5.0 mL). The reactionmixture was stirred at room temperature for 30 min. The mixture was thenneutralized with aqueous 1.0 N HCl solution (800.0 μL) and diluted withEtOAc (60 mL). The solution was successively washed with water andbrine, dried (MgSO₄), filtered and concentrated under reduced pressureto give compound 18.5 (149 mg, 97% yield) as a yellow oil.

f) Compound 1007

To a solution of compound 18.5 (75.0 mg, 249 μmol) in CH₂Cl₂ (5 mL) atroom temperature was added (COCl)₂ (43.5 μL, 499 μmol) followed by DMF(5 μL). The reaction mixture was stirred for 15 min and was thenconcentrated under reduced pressure. The resulting acyl chloride wasdissolved in THF (3 mL) and a solution of compound 2.5 (Example 2) (82.5mg, 299 μmol) in THF (2 mL) was added followed by pyridine (60.5 μL, 748μmol). The reaction mixture was stirred for 10 min and then quenchedwith a few drops of aqueous 0.1 N HCl solution. The reaction mixture wasthen concentrated under reduced pressure. The intermediate ester wasdiluted in DMSO (6 mL) and treated with aqueous 1.0N NaOH solution (1.0mL, 1.0 mmol). The reaction mixture was stirred for 3 h and thenneutralized with TFA. The solution was purified by RP-HPLC and the purefractions were concentrated to give compound 1007 (32.4 mg, 24% yield)as a white solid. ¹H NMR (DMSO-d₆) δ 12.34 (broad s, 1H), 10.00 (s, 1H),7.81-7.79 (m, 2H), 7.66-7.63 (m, 3H), 7.53 (s, 1H), 7.45 (d, J=7.8 Hz,1H), 7.36-7.32 (m, 3H), 4.21 (s, 2H), 3.61 (s, 2H), 2.40 (s, 3H).

Example 19 (Entry 1008) (Bl 211786)

a) Compound 19.1

To a suspension of MeONa (384 mg, 7.12 mmol) in THF (18 mL) at roomtemperature was added ethyl formate (574.9 μL, 7.12 mmol) followed by asolution of 2-chloro-4-methylacetophenone (1.00 g, 5.93 mmol) in THF(6.0 mL). The reaction mixture was stirred at room temperature for 16 h,and then aqueous 1.0 N NaOH solution (60 mL) was added. The aqueousphase was washed with Et₂O (2×2 mL). These extracts were discarded, andthe aqueous phase was acidified with aqueous 1.0 N HCl solution (65 mL).The mixture was then extracted with Et₂O (3×40 mL). The combined organicextracts were washed with water and brine, dried (MgSO₄), filtered, andconcentrated under reduced pressure to give compound 19.1 (1.11 g, 95%yield) as a yellow oil.

b) Compound 19.2

Hydrazine hydrate (193.2 μL, 6.20 mmol) was added dropwise to a cold (0°C.) solution of compound 19.1 (1.11 g, 5.64 mmol) in ethanol (15.0 mL).The cooling bath was then removed and the reaction mixture was stirredat room temperature for 3 h. The mixture was concentrated under reducedpressure and the residue diluted in CH₂Cl₂ (150 mL). The solution waswashed with brine, dried (MgSO₄), filtered and concentrated underreduced pressure. The crude product was purified by flash chromatography(CH₂Cl₂:(CH₃)₂CO, 95:5) to afford compound 19.2 (671 mg, 62% yield) as ayellow solid.

c) Compound 19.3

A solution of bromine (198 μL, 3.83 mmol) in CH₂Cl₂ (10 mL) was addeddropwise to a solution of compound 19.2 (671 mg, 3.48 mmol) in CH₂Cl₂(20 mL). The reaction mixture was stirred at room temperature for 1 h.The mixture was diluted with CH₂Cl₂ (60 mL) and the resulting solutionwas successively washed with water, aqueous saturated NaHCO₃ solutionand brine, dried (MgSO₄), filtered and concentrated under reducedpressure. The crude product was purified by flash chromatography(CH₂Cl₂:(CH₃)₂CO, 95:5) to afford compound 19.3 (382 mg, 40% yield) as ayellow solid.

d) Compound 19.4

NaH (60% in oil) (59.9 mg, 1.50 mmol) was added to a cold (0° C.)solution of compound 19.3 (369.6 mg, 1.36 mmol) in DMF (5 mL). Thereaction mixture was stirred at 0° C. for 30 min and then MeI (93.2 μL,1.50 mmol) was added. The mixture was warmed to room temperature andstirred for 1 h. The reaction mixture was diluted with EtOAc (100 mL)and washed with water and brine, dried (MgSO₄), filtered andconcentrated under reduced pressure. The crude product was purified byflash chromatography (CH₂Cl₂:(CH₃)₂CO, 95:5) to afford compound 19.4(363 mg, 93% yield; 1.6:1 mixture of isomers) as a yellow solid.

e) Compound 19.5

To a cold (−78° C.) solution of compound 19.4 (75.0 mg, 262 μmol) in THF(4 mL) was added 2.5 M n-BuLi in hexane (115.6 μL, 288.9 μmol). After 15min, a solution of (i-Pr₃SiS)₂ (199.0 mg, 525.3 μmol) in THF (1 mL) wasadded via cannula to the reaction mixture at −78° C. The reactionmixture was stirred for 15 min and then the cooling bath was removed andthe solution stirred for 3 h. CH₂Cl₂ (50 mL) was added and the mixturewas washed with water and brine, dried (MgSO₄), filtered andconcentrated under reduced pressure to afford compound 19.5 (46.4 mg,45% yield).

f) Compound 19.6

TBAF (1.0 M in THF) (294 μL, 294 μmol) was added to a solution ofcompound 19.5 (46.4 mg, 117 μmol) and tert-butyl bromoacetate (43.4 μL,294 μmol) in DMF (3 mL). The reaction mixture was stirred for 30 min,quenched with water (10 mL), and diluted with EtOAc (60 mL). The organicphase was washed with water and brine, dried (MgSO₄), filtered andconcentrated under reduced pressure. The crude product was purified byflash chromatography (CH₂Cl₂:(CH₃)₂CO, 95:5) to afford compound 19.6(34.8 mg, 84% yield) as a yellow oil.

g) Compound 19.7

TFA (1.0 mL, 13.0 mmol) was added dropwise to a solution of compound19.6 (34.8 mg, 98.6 μmol) in CH₂Cl₂ (2 mL) at room temperature. Thereaction mixture stirred for 8 h and then concentrated under reducedpressure. The intermediate acid was diluted in CH₂Cl₂ (5 mL) and (COCl)₂(25.8 μL, 295.8 μmol) was added followed by DMF (5 μL). The reactionmixture was stirred for 15 min and CH₂Cl₂ was removed under reducedpressure. The intermediate acyl chloride was dissolved in THF (3 mL) anda solution of compound 2.5 (Example 2) (40.8 mg, 147.9 μmol) in THF (1mL) was added followed by pyridine (23.9 μL, 295.8 μmol). The reactionmixture was stirred for 1 h and then concentrated under reduced pressureto give compound 19.7 (50 mg, 91% yield).

h) Compound 1008

Ester 19.7 (50 mg, 90 μmol) was dissolved in DMSO (4 mL) and aqueous 1 NNaOH (500 μL, 500 μmol) solution was added to the solution. The reactionmixture was stirred at room temperature for 1 h and then acidified(pH=2) with TFA. The solution was purified by RP-HPLC and the purefractions containing the desired isomer (slowest eluting isomer) wereconcentrated to give compound 1008 (18.8 mg, 39% yield). ¹H NMR(DMSO-d₆) 612.35 (broad s, 1H), 9.43 (s, 1H), 7.88 (d, J=8.6 Hz, 1H),7.76 (d, J=2.0 Hz, 1H), 7.65-7.62 (m, 4H), 7.41 (s, 1H), 7.35 (d, J=8.0Hz, 2H), 7.28 (d, J=7.8 Hz, 1H), 7.17 (d, J=7.2 Hz, 1H), 3.61 (s, 2H),3.56 (s, 3H), 3.49 (s, 2H), 2.33 (s, 3H).

Example 20 (Entry 1009) (Bl 211844)

a) Compound 20.1

1-Amino-2,2-ethylenedioxypropane (2.00 g, 17.0 mmol) was added to acooled (0° C.) solution of compound 17.1 (Example 17) (3.17 g, 17.1mmol) in ethanol (14 mL). The reaction mixture was stirred at reflux for30 min and then cooled to 0° C. (product precipitated as a white solid).Aqueous 12 N HCl solution (1.4 mL) was added and the mixture was againheated under reflux for 1 h (solution after heating). The solution wascooled to room temperature and the precipitate was collected by suctionfiltration to give compound 20.1 (2.01 g, 49% yieldl) as a white solid.

b) Compound 20.2

To a solution of compound 20.1 (90.3 mg, 378 μmol) in DMF (5 mL) wasadded K₂CO₃ (157 mg, 1.13 mmol) followed by the methyl ester analog ofcompound 2.6 (Example 2) (150 mg, 378 μmol). The reaction mixture wasstirred at room temperature for 2 h. The mixture was then diluted withEtOAc (100 mL) and successively washed with water and brine, dried(MgSO₄), filtered and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography (CH₂Cl₂:(CH₃)₂CO, 95:5) toafford compound 20.2 (172 mg, 82% yield) as a white solid.

c) Compound 1009

Using a method similar to the one described in Example 19, Step h,compound 20.2 (165 mg, 298 μmol) gave compound 1009 (160 mg, 99% yield)as a white solid. ¹H NMR (DMSO-d₆) δ 10.14 (s, 1H), 7.95 (d, J=8.4 Hz,1H), 7.79 (d, J=2.0 Hz, 1H), 7.66-7.63 (m, 4H), 7.50 (d, J=8.1 Hz, 1H),7.37-7.33 (m, 4H), 4.03 (s, 2H), 3.63 (s, 2H), 2.42 (s, 3H), 1.98 (s,3H).

Example 21 (Entry 1010) (Bl 211867)

a) Compound 21.1

To a solution of 2-chloro-4-methylbenzoic acid (3.21 g, 18.8 mmol) inCH₂Cl₂ (80 mL) at room temperature was added (COCl)₂ (3.28 mL, 37.6mmol) followed by DMF (100 μL). The reaction mixture was stirred for 3 hthen was concentrated under reduced pressure. The intermediate acylchloride was dissolved in THF (40 mL) and added dropwise to a cold (0°C.) solution of CH₂N₂ in Et₂O (ca. 0.6 M, 75 mL). The reaction mixturewas stirred at room temperature for 4 h. The solvent was then carefullyremoved under reduced pressure and the residue dissolved in MeOH (100.0mL). Ag₂O (4.35 g, 18.8 mmol) was added to the solution and the reactionmixture was stirred at 0° C. for 1 h and then heated at 60° C. for 2 h.The reaction mixture was then cooled to room temperature and filteredthrough diatomaceous earth. The filtrate was concentrated under vacuumand the residue purified by flash chromatography (hexane:EtOAc, 8:2) toafford compound 21.1 (588 mg, 16% yield).

b) Compound 21.2

tert-Butoxybis(dimethylamino)methane (685 μL, 3.32 mmol) was added to asolution of compound 21.1 (589 mg, 2.96 mmol) in THF (7 mL) at roomtemperature. The reaction mixture was stirred at room temperature for 2h then was concentrated under reduced pressure. The residue was purifiedby flash chromatography (hexane:EtOAc, 1:1) to afford compound 21.2(38.3 mg, 72% yield) as an orange oil.

c) Compound 21.3

Hydrazine monohydrate (113 μL, 2.33 mmol) was added to a solution ofcompound 21.2 (538 mg, 2.12 mmol) in ethanol (5 mL). The reactionmixture was stirred at reflux for 3 h. The mixture was then concentratedunder reduced pressure to give compound 21.3 (439 mg, 93% yield) as ayellow solid.

d) Compound 21.4

BBr₃ (1.0 M in CH₂Cl₂, 8.12 mL, 8.12 mmol) was added to a cold (0° C.)solution of compound 21.3 (452.3 mg, 2.03 mmol) in CH₂Cl₂ (20.0 mL). Thereaction mixture was heated to room temperature and stirred for 3 h. Themixture was then cooled to 0° C. and quenched with MeOH (5 mL). Thesolution was diluted with CH₂Cl₂ (100 mL) and successively washed withwater, aqueous saturated NaHCO₃ and brine, dried (MgSO₄), filtered andconcentrated under reduced pressure to give compound 21.4 (238 mg, 56%yield).

e) Compound 1010

To a solution of compound 21.4 (60.0 mg, 287.6 μmol) in DMF (5 mL) atroom temperature was added CsCO₃ (281.1 mg, 862.7 μmol) followed bycompound 2.6 (Example 2) (114.1 mg, 287.6 μmol). The reaction mixturewas stirred at 50° C. for 2 h. The mixture was then filtered throughdiatomaceous earth and to the filtrate was added aqueous 1 N NaOHsolution (1.0 mL, 1.0 mmol). The reaction mixture was stirred at roomtemperature for 30 min and acidified (pH=2) with TFA. The solution waspurified by RP-HPLC and the pure fractions were concentrated to givecompound 1010 (6.8 mg, 5% yield) as a yellow solid. ¹H NMR (DMSO-d₆) δ12.40 (broad s, 1H), 9.20 (s, 1H), 8.13 (d, J=8.6 Hz, 1H), 7.79 (d,J=1.9 Hz, 1H), 7.67-7.62 (m, 4H), 7.42 (d, J=7.9 Hz, 1H), 7.38 (s, 1H),7.34 (d, 8.2 Hz, 2H), 7.21 (d, J=7.7 Hz, 1H), 4.64 (s, 2H), 3.60 (s,2H), 2.34 (s, 3H).

Example 22 (Entry 1015) (Bl212043)

a) Compound 22.2

To a cold (−78° C.) solution of compound 22.1 (2.50 g, 11.8 mmol) in THF(50 mL) was added 1.0 M LiHMDS in hexane (24.7 mL, 24.7 mmol). Thereaction mixture was stirred at −78° C. for 1 h and then aceticanhydride (1.33 mL, 14.1 mmol) was added dropwise. The reaction mixturewas warmed to room temperature and stirred for 30 min. The mixture wasthen poured in aqueous 1 N HCl solution (50 mL), and extracted withEtOAc (2×50 mL). The organic extracts were washed with water, brine,dried (MgSO₄), filtered and concentrated under vacuum. The crude productwas purified by flash chromatography (hexane:EtOAc, 8:2) to affordcompound 22.2 (2.37 g, 79% yield) as a clear oil.

b) Compound 22.3

Hydrazine hydrate (122 μL, 3.93 mmol) was added to a solution ofcompound 22.2 (500 mg, 1.96 mmol) in ethanol (3.0 mL). The reactionmixture was stirred under reflux for 2 h. The reaction mixture was thencooled to room temperature and the white precipitate was collected undersuction filtration to give compound 22.3 (255 mg, 59% yield).

c) Compound 1015

Using a method analogous to the one described in Example 2, Step g,compound 22.3 (24.8 mg, 111 μmol) and benzyl4-[4-(2-bromoacetamido)-3-chlorophenyl]-2,2-dimethylbut-3-ynoate (50.0mg, 111 μmol) (prepared from the benzyl ester analog of compound 4.3 andbromoacetyl bromide using a method similar to the one described inExample 2, Step f) gave compound 1015 (19.1 mg, 34% yield) as a whitesolid. ¹H NMR (DMSO-d₆) 612.88 (broad s, 1H), 11.96 (s, 1H), 9.18 (s,1H), 8.11 (d, J=8.5 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.36 (d, J=1.8 Hz,1H), 7.34 (s, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 4.79(s, 2H), 2.32 (s, 3H), 2.07 (s, 3H), 1.45 (s, 6H).

Example 23 (Entry 1017) (Bl 212144)

a) Compound 23.1

To a solution of compound 2.3 (Example 2) (600 mg, 3.58 mmol) in MeCN(15 mL) at room temperature was added Et₃N (1.1 mL, 7.9 mmol) followedby thiophosgene (300 μL, 3.94 mmol). The reaction mixture was stirred atroom temperature for 3 h. The mixture was diluted with EtOAc (100 mL)and successively washed with water and brine, dried (MgSO₄), filteredand concentrated under reduced pressure to afford compound 23.1 (750 mg,100% yield) as a brown oil.

b) Compound 23.2

To a solution of compound 23.1 (150 mg, 715 μmol) in EtOH (15. mL) wasadded trifluoroacetylhydrazine (101 mg, 787 μmol) and the reactionmixture was stirred at reflux for 2 h. The mixture was then concentratedunder reduced pressure and the residue diluted with TFA (10 mL). Themixture was stirred at reflux for 2 h and the excess TFA was removedunder reduced pressure. The mixture was diluted with EtOAc (50 mL) andsuccessively washed with saturated aqueous NaHCO₃, water and brine,dried (MgSO₄), filtered and concentrated under reduced pressure. Thecrude product was purified by flash chromatography (CH₂Cl₂:(CH₃)₂CO,9:1) to afford compound 23.2 (134 mg, 59% yield) as a pale yellow solid.

c) Compound 1017

Using a method analogous to the one described in Example 22, Step c,compound 23.2 (49.1 mg, 153.6 μmol) gave compound 1017 (59.0 mg, 64%yield) as a white solid. ¹H NMR (DMSO-d₆) δ 9.97 (s, 1H), 7.83 (d, J=8.4Hz, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.52 (d, J=1.8 Hz, 1H), 7.51 (d, J=1.9Hz, 1H), 7.35 (dd, J=8.4, 1.8 Hz, 1H), 7.28 (dd, J=8.2, 1.8 Hz, 1H),4.35 (s, 2H), 2.08-2.02 (m, 1H), 1.45 (s, 6H), 1.09-1.05 (m, 2H),0.87-0.83 (m, 2H).

Example 24 Reverse Transcriptase (RT) Assays

Enzymatic Assay (IC₅₀)

The enzymatic assay employed is described as follows: The reversetranscriptase (RT) enzyme assay has been adapted to a 96-well microtiterplate format and uses PicoGreen™ as a fluorescent intercalator. Moreexplicitly, the HIV-1 RT enzyme was thawed and appropriately dilutedinto Tris/HCl 50 mM pH 7.8 containing NaCl 60 mM, MgCl₂.6H₂O 2 mM, DTT 6mM, GSH 2 mM and 0.02% w/v Chaps to give ≈10 nM enzyme. To 10 μL of thisenzyme solution was added 10 μL of inhibitor solution (40 μM to 2.032 nMinhibitor in the same assay buffer as above containing 4% v/v DMSO). Theplate was pre-incubated for 15 minutes at room temperature beforeproceeding to the next step. In this pre-incubation step, the highestand lowest inhibitor concentrations were 20 μM and 1.016 nM respectivelyand the concentration of DMSO was 2% v/v. Then the enzymatic reactionwas initiated by addition of 20 μL of substrate solution. The finalreaction mixture contained Tris/HCl 50 mM pH 7.8, NaCl 60 mM, MgCl₂.6H₂O2 mM, DTT 6 mM, GSH 2 mM, CHAPS 0.02% w/v, DMSO 1% v/v, poly rC 45 nM,dG₁₅ 4.5 nM, dGTP 3.6 μM, and 2.5 nM enzyme. In this incubation step,the highest and lowest inhibitor concentrations were 10 μM and 0.508 nMrespectively. After addition of the substrate cocktail, the plate wascovered with a plastic seal and incubated for 50 minutes at 37° C. in adry incubator. The reaction was then quenched by addition of 5 μL ofEDTA 0.5 M. The plate was shaken for 30 seconds at medium speed andincubated for 5 minutes at room temperature. Then 160 μL of PicoGreen™1:400 dilution from commercial stock (diluted in Tris 20 mM pH 7.5 withEDTA 1 mM) was added and the plate was shaken for 30 seconds andincubated for 10 minutes at room temperature. The plate was thenanalyzed using a POLARstar Galaxy fluorometer (BMG Labtechnologies) withλ_(ex) and λ_(em) of 485 nm and 520 nm respectively. Each well was readfor 1.25 second. Each row contained at its extremities a blank and acontrol well.

P24 Cellular Assay (EC₅₀)

The p24 assay is as described in WO 01/96338.

C8166 HIV-1 Luciferase Assay (EC₅₀)

Plasmid: pGL3 Basic LTR/TAR #12

Plasmid is the pGL3 Basic Vector (a promoterless luciferase expressionvector from Promega catalogue #E1751) with the addition of HIV-1 HxB2LTR sequence from nucleotide −138 to +80 (Sca1-HindIII) upstream of theluciferase gene and the gene for blasticidine resistance cloned in.

Cells: C8166 LTRIuc #A8-F5-G7

C8166 cells are a human T-lymphotrophic virus type 1 immortalized butnonexpressing line of cord blood lymphocytes and are highly permissiveto HIV-1 infection. The reporter cells were made by electroporatingC8166 cells with pGL3 Basic LTR/TAR and then selecting positive cloneswith blasticidine. The clone C8166-LTRluc #A8-F5-G7 was selected by 3consecutive rounds of limiting dilution under blasticidine selection.

Media: Complete media consisting of: RPMI 1640+10% FBS+10⁻⁵ Mβ-mercaptoethanol+10 μg/mL gentamycin. Cultures are maintained incomplete media with 5 μg/mL blasticidine, however, selection is removedfor the assay.

Luciferase Assay Protocol

Preparation of Compounds

Serial dilutions of HIV-1 inhibitor compounds are prepared in completemedia from 10 mM DMSO stock solutions. Eleven serial dilutions of 2.5×are made at 8× desired final concentration in a 1 mL deep well titerplate (96 wells). The 12^(th) well contains complete media with noinhibitor and serves as the positive control. All samples contain thesame concentration of DMSO (≦0.1% DMSO). A 25 μL aliquot of inhibitor isadded, to triplicate wells, of a 96 well tissue culture treated clearview black microtiter plate (Corning Costar catalogue # 3904). The lastrow is reserved for uninfected C8166 LTRIuc cells to serve as thebackground blank control and the first row is media alone.

Infection of Cells

Count C8166 LTRluc cells and place in a minimal volume of complete RPMI1640 in a tissue culture flask (ex. 30×10⁶ cells in 10 ml media/25 cm²flask). Infect cells with HIV-1 at a moi of 0.005. Incubate cells for1.5 h at 37° C. on a rotating rack in a 5% CO₂ incubator. Resuspendcells in complete RPMI to give a final concentration of 25,000-cells/175μL. Add 175 μL of cell mix to wells of 96 well microtiter platecontaining 25 μL 8× inhibitors. Add 25,000 uninfected C8166-LTRluccells/well in 200 μL complete RPMI to last row for background control.Incubate cells at 37° C. in 5% CO₂ incubator for 3 days.

Luciferase Assay

Add 50 μL Steady Glo (luciferase substrate T_(1/2)=5 h Promega catalogue# E2520) to each well of the 96 well plate. Determine the relative lightunits (RLU) of luciferase using the BMG LUMIstar Galaxy luminometer.Plates are read from the bottom for 2 seconds per well with a gain of240.

The level of inhibition (% inhibition) of each well containing inhibitorwas calculated with the following equation:

${\% \cdot {inhibition}} = {\left( {1 - \left\lbrack \frac{{{RLU} \cdot {well}} - {{RLU} \cdot {blank}}}{{{RLU} \cdot {control}} - {{RLU} \cdot {blank}}} \right\rbrack} \right)*100}$

The calculated % inhibition values were then used to determine EC₅₀,slope factor (n) and maximum inhibition (I_(max)) by the non-linearregression routine NLIN procedure of SAS using the following equation:

${\% \cdot {inhibition}} = \frac{I_{\max} \times \lbrack{inhibitor}\rbrack^{n}}{\lbrack{inhibitor}\rbrack^{n} + {IC}_{50}^{n}}$

TABLES

Tables 1 to 7 illustrate further compounds of the present invention,which can be synthesized in analogy to the methods as describedhereinbefore, optionally modified by procedures known to the one skilledin the art. All compounds shown in the tables show IC₅₀ values in theenzymatic assay described in Example 24 of less than 1 μM against theK103NNY181C mutant reverse transcriptase. As well, most compounds shownin Tables 1 to 7 below show IC₅₀ values in the enzymatic assay describedin Example 24 of less than 1 μM against the wild type HIV reversetranscriptase. All compounds shown in Tables 1 to 7 below are alsoactive in at least one of the cellular assays described in Example 24.

Retention times (t_(R)) for each compound were measured using thestandard analytical HPLC conditions described in the Examples. As iswell known to one skilled in the art, retention time values aresensitive to the specific measurement conditions. Therefore, even ifidentical conditions of solvent, flow rate, linear gradient, and thelike are used, the retention time values may vary when measured, forexample, on different HPLC instruments. Even when measured on the sameinstrument, the values may vary when measured, for example, usingdifferent individual HPLC columns, or, when measured on the sameinstrument and the same individual column, the values may vary, forexample, between individual measurements taken on different occasions.

TABLE 1

IC₅₀ t_(R) MS mut BI21 Cpd R¹—Ar X R⁴ (min) (MH⁺) (nM) 1421 1001

S

6.9 599.1601.1603.1 25.5 1469 1002

S

6.5 543.0544.0547.0 795 1531 1003

O

6.4 510.1512.1514.0 770 1546 1004

S

6.2 526.0528.0530.0 420 1584 1005

S

6.6 527.1529.1531.0 730 1585 1006

S

8.1 568.1570.1572.0 216 1689 1007

S

7.4 542.0544.0546.0(M − H)⁻ 107 1786 1008

S

6.8 541.0543.0545.0 178 1844 1009

S

5.4 540.1542.1544.0 549 1867 1010

O

6.2 510.1512.0 156 1907 1011

S

6.1 572.1574.1576.0 21 1936 1012

S

6.7 544.1546.1548.0 389 1938 1013

S

5.5 636.2638.2640.0 75 1939 1014

S

5.3 622.2624.2626.0 81 2043 1015

O

6.6 500.1502.1504.0 48 2045 1016

O

6.3 472.1474.1476.0 48 2144 1017

S

8.8 597.1599.1602.0 72 2148 1018

S

7.4 689.2691.2693.0 51 2207 1019

S

7.5 569.1571.1573.0 525

TABLE 2

IC₅₀ t_(R) MS mut BI21 Cpd R¹ R² R³ R⁴¹ (min) (MH⁺) (nM) 1175 2001

Cl H —COOMe 6.0 528.1530.0532.0 133 1176 2002

Cl H —COOH 5.2 514.0516.0518.0 53 1177 2003

Cl H —CH₂COOMe 5.9 542.1544.0546.0 53 1178 2004

Cl H —CH₂COOH 5.3 528.0530.0532.0 48 1285 2005

Cl H —OMe 9.3 500.1502.1504.0 78 1288 2006

Cl H —OH 7.7 486.0488.0490.0 29 1298 2007

Cl H —O—CH₂COOH 7.5 544.0546.0548.0 22 1302 2008

Cl H —COOMe 8.3 570.0572.1574.1 39 1309 2009

Cl H —CH₂CH₂OH 7.6 514.1516.1518.0 28 1317 2010

NO₂ H —CH₂COOMe 8.7 553.1555.1 40 1321 2011

NO₂ H —CH₂COOH 7.4 539.1541.1 49 1322 2012

Cl H —CH₂CONH₂ 6.8 527.1529.1631.0 15 1323 2013

NO₂ H —CH₂CONH₂ 6.8 538.1540.1 20 1331 2014

NO₂ H —SO₂NH₂ 6.9 560.0562.0 69 1361 2015

Cl H —CH₂COOH 7.6 570.1572.1574.0 28 1380 2016

Cl H —O—CH₂COOH 7.6 586.0588.0590.0 22 1426 2017

Cl H —CH₂CONHSO₂Me 6.6 605.0607.0609.0 38 1533 2018

Cl H —O—CH₂COOH 7.5 620.1622.1624.0 12 1549 2019

Cl H —C(Me)₂COOH 7.7 598.1600.1602.0 33 1560 2020

Cl H —CH₂COOH 7.6 604.0606.0608.0 18 1561 2021

Cl H —CH₂COOH 6.9 540.0542.0544.0(M − H)⁻ 20 1562 2022

Cl H

6.5 641.2643.2645.2 42 1565 2023

Cl H —CH₂COOH 6.9 582.0584.0586.0 169 1576 2024

Cl H

6.1 627.3629.3631.0 26 1577 2025

Cl H —C(Me)₂COOH 7.3 570.1572.1574.0 42 1578 2026

Cl H —C(Me)₂COOH 7.1 574.1576.1578.1 48 1590 2027

Cl H —SO₂Me 8.7 588.0590.0592.1(M − H)⁻ 23 1591 2028

Cl H —CH₂CH₂COOH 8.8 582.1584.1586.1(M − H)⁻ 9.3 1592 2029

Cl H

6.1 625.1627.2629.2 19 1678 2030

Cl H —CH₂COOH 7.7 564.1566.1568.1 64 1679 2031

Cl H

5.7 655.3657.3658.2 34 1690 2032

Cl H

8.7 580.1582.1582.0(M − H)⁻ 6.6 1695 2033

Cl H —CH₂COOH 7.4 554.2556.2558.2 15 1732 2034

Cl H —CH₂COOH 6.9 598.1600.1602.1 178 1737 2035

Cl H —CH₂COOH 5.4 571.0573.0575.0 269 1744 2036

Cl H

5.9 622.2624.2626.0 67 1745 2037

Cl H —CH₂COOH 7.3 624.1626.1628.1 49 1751 2038

Cl H —CH₂COOH 7.4 562.0564.0566.0(M − H)⁻ 16 1760 2039

Cl H

6.1 639.2641.2643.3 28 1774 2040

Cl H

5.7 683.1685.1687.1 36 1775 2041

Cl H

5.8 641.1643.1645.0 28 1777 2042

Cl H

5.7 641.2643.2645.0 15 1778 2043

Cl H

5.9 657.2659.2661.0 32 1809 2044

Cl H —CH₂COOH 6.9 594.0596.0598.0(M − H)⁻ 29 1896 2045

Cl H —CH₂COOH 6.9 554.1556.1558.1 16 1946 2046

Cl H

6.2 609.2611.2613.2 6.95 1947 2047

Cl H

6.3 623.1625.1627.1 63.5 1948 2048

Br H —CH₂COOH 6.7 598.0600.0602.0 13 1981 2049

Cl H

5.8 651.1653.1655.0 54 2004 2050

Cl H

5.9 651.1653.1655.1(M − H)⁻ 359 2013 2051

Cl F

6.1 641.1643.1645.1 30.5 2032 2052

Cl H —C(Me)₂COOH 7.0 582.1584.1586.0 19 2035 2053

Cl H

6.2 655.1657.1659.0 24 2047 2054

Cl H

5.9 669.1671.1673.0 69.5 2052 2055

Cl H —C(Me)₂COOH 7.2 582.1584.1586.0(M − H)⁻ 56 2063 2056

Cl H

6.1 611.2613.2615.0 29 2124 2057

Cl F

5.9 627.2629.2631.0 8.8 2125 2058

Cl F

5.7 655.1657.1659.0 25 2257 2059

Cl F

5.9 691.0693.0695.0 13

TABLE 3

t_(R) MS IC₅₀ BI21 Cpd R¹ R⁴ (min) (MH⁺) mut (nM) 1283 3001

9.3 528.0530.0532.0 146 1284 3002

9.0 542.1544.1546.1 120 1286 3003

7.7 512.0514.0516.0(M − H)⁻ 241 1287 3004

7.7 528.0530.0532.0 93 1299 3005

8.2 478.0480.0482.0 305 1300 3006

6.7 464.0466.0468.0 265 1318 3007

—CONHMe 6.1 451.0453.0455.0 290 1320 3008

—CONHEt 6.4 465.0467.0469.0 300 1383 3009

7.8 619.9621.9623.9 154 1439 3010

7.7 600.1602.1604.1 33 1440 3011

7.8 598.0600.0602.0(M − H)⁻ 340 1441 3012

7.6 601.1606.1608.1 36 1473 3013

7.7 617.9619.9621.0(M − H)⁻ 24 1513 3014

8.9 477.1479.0481.1 142 1514 3015

5.0 492.1494.1496.0 185 1516 3016

6.3 461.1463.1465.0 359 1517 3017

6.4 475.1477.1479.0 308 1518 3018

4.7 460.1462.1464.0 269 1532 3019

5.5 462.1464.0466.0 539 1552 3020

7.4 604.1606.1608.1 23 1570 3021

—SO₂NHMe 7.9 529.1531.0533.0 63 1664 3022

7.4 556.1558.1560.0 50 1668 3023

—SO₂NHCH(Me)₂ 10.4 557.1559.1561.0 284 1669 3024

11.2 619.2621.2623.2 516 1670 3025

—SO₂N(Me)₂ 10.5 543.1545.1547.1 217 1671 3026

10.8 591.2593.2595.2 423 1673 3027

—SO₂NH(CH₂)₂OH 8.7 559.1561.1563.1 81 1676 3028

11.0 605.1607.1610.0 440 1733 3029

5.7 502.0504.0506.0 76 1763 3030

8.0 562.0564.0566.0 28 1784 3031

8.4 586.1588.1590.0 15.5 1889 3032

—SO₂NHCH₂COOH 6.3 571.0573.0575.0 97.5 1937 3033

5.7 563.1565.1567.1 201 1943 3034

5.4 565.2567.2569.0 111.5 1944 3035

5.7 619.1621.1623.0(M − H)⁻ 355 1983 3036

5.1 582.0584.1586.0 88 1986 3037

5.0 597.1599.1601.1 112 2014 3038

6.3 657.1659.1661.1 167 2038 3039

5.5 554.0556.0558.0(M − H)⁻ 267.5 2062 3040

5.9 555.0557.0559.0(M − H)⁻ 236.5 2183 3041

7.6 504.0506.0508.0 94 2199 3042

7.4 609.0611.0613.0(M − H)⁻ 387 2208 3043

5.9 576.0578.0580.0 2209 3044

9.0 518.0520.0522.0 58.5 2282 3045

5.9 516.2518.1520.1 380.5 2382 3046

7.2 536.1538.1540 105.5

TABLE 4

IC₅₀ t_(R) MS mut BI21 Cpd R¹ R² R³ R⁹ (min) (MH⁺) (nM) 1542 4001

Cl H —(CH₂)₂OH 7.3 504.3506.3508.3 16 1557 4002

Cl H

8.7 536.1538.1540.1 268 1563 4003

Cl H —(CH₂)₄OH 8.4 532.1534.1536.0 643 1566 4004

Cl H —(CH₂)₃OH 6.4 518.1520.1522.1 16 1567 4005

Cl H —C(Me)₂OH 6.4 518.15201522.1 20 1571 4006

Cl H —CH₂OH 6.0 490.2492.2494 11 1583 4007

Cl H —C(Me)₂OH 5.8 490.2492.1494.0 38 1661 4008

Cl H —CH₂N(Et)₂ 5.5 545.2547.2549.2 94 1672 4009

Cl H —(CH₂)₂CH₃ 8.1 502.1504.1506.1 8.9 1675 4010

Cl H

5.3 559.1561.1563.2 27 1677 4011

Cl H —C(Me)₂CO₂H 6.5 546.1548.1550.0 25 1683 4012

Cl H

5.5 543.2545.2547.2 46 1686 4013

Cl H

5.8 658.3660.3662.0 62 1687 4014

Cl H

5.6 557.2559.2561.2 88 1688 4015

Cl H

5.4 572.2574.2576.2 40 1692 4016

Cl H —C(Me)₂CH₂OH 6.6 532.2534.2536.2 35 1729 4017

Cl H

6.8 585.2587.2589.2 41 1730 4018

Cl H —C(Me)₂OH 5.9 502.1504.1506.1 17 1731 4019

Cl H —C(Me)₂COOH 6.0 530.1532.1534.1 22 1736 4020

Cl H

7.1 574576578(M − H)⁻ 33 1752 4021

Cl H —C(Me)₂OH 5.7 487.0489.0491.0 361 1753 4022

Cl H —C(Me)₂OH 6.6 548.0550.0552.0 185 1755 4023

Cl H

5.8 658.2660.2662.2 64 1756 4024

Cl H

7.2 665.2667.2669.2(M − H)⁻ 35 1757 4025

Cl H

7.3 693.2695.2697.2(M − H)⁻ 44 1758 4026

Cl H

6.3 719.2721.2723.2(M − H)⁻ 63 1759 4027

Cl H

6.9 685.2687.2689.2(M − H)⁻ 26 1761 4028

Cl H —C(Me)₂OH 6.8 542.0544.0546.0(M − H)⁻ 256 1764 4029

Cl H —C(Me)₂OH 6.7 548.0550.0552.0 212 1765 4030

Cl H —C(Me)₂OH 6.9 542.0544.0546.0(M − H)⁻ 21 1766 4031

Cl H —C(Me)₂OH 6.9 542.0544.0546.0(M − H)⁻ 264 1767 4032

Cl H

7.4 500.1502.1504.1 39 1779 4033

Cl H

6.5 575.1577.1579.1 36 1783 4034

Cl H —CH₂OC(O)NH₂ 6.0 533.1535.0537.0 8.9 1787 4035

Cl H

6.0 633.2635.2637.2 56 1788 4036

Cl H

7.2 657.2659.2661 36 1789 4037

Cl H

7.7 653.2655.2657(M − H)⁻ 66 1790 4038

Cl H

7.4 627.2629.2631.0(M − H)⁻ 75 1791 4039

Cl H

7.3 643.2645.2647.0(M − H)⁻ 40 1792 4040

Cl H

7.7 653.2655.2657.0 58 1793 4041

Cl H

6.1 652.2654.2656.0 35 1794 4042

Cl H

7.1 573.2575.2577.0(M − H)⁻ 37 1795 4043

Cl H

6.8 654.3(M + Na) 35 1796 4044

Cl H

8.0 649.2651.2653.0(M − H)⁻ 296 1797 4045

Cl H

7.5 693.2695.2697.0(M − H)⁻ 32 1798 4046

Cl H

7.2 659.2661.2663.0(M − H)⁻ 23 1799 4047

Cl H

5.8 646.3648.3650.0 66 1800 4048

Cl H

6.9 617.2619.2621.0(M − H)⁻ 26 1801 4049

Cl H

7.3 601.2603.2605.0(M − H)⁻ 30 1802 4050

Cl H

6.9 603.2605.2607.0(M − H)⁻ 66 1803 4051

Cl H

7.3 587.2589.2591.0(M − H)⁻ 35 1804 4052

Cl H

7.0 631.2633.2635.0(M − H)⁻ 30 1805 4053

Cl H

7.2 645.2647.2649.0(M − H)⁻ 25 1806 4054

Cl H

7.7 640.2642.2644.0(M − H)⁻ 35 1807 4055

Cl H

7.0 645.2647.2649.0(M − H)⁻ 15 1808 4056

Cl H

6.6 631.2633.2635.0(M − H)⁻ 26 1834 4057

Me H —C(Me)₂COOH 6.1 524.1526.0528.0 96 1843 4058

Cl H —C(Me)₂COOH 7.0 570.0572.0574.0 63 1865 4059

Cl H —C(Me)₂OH 6.7 544.1546.1548.0 656 1866 4060

Cl H —C(Me)₂OH 6.8 544.1546.1548.0 42 1870 4061

Cl H —(CH₂)₃OC(O)NH₂ 6.3 561.1563.1565.0 16 1874 4062

Cl H

6.4 530.1532.1534.0 53 1878 4063

Cl H —C(Me)₂COOH 6.9 572.1574.1576.0 51.5 1892 4064

Cl H

6.9 559.1561.1563.1 11.5 1897 4065

Cl H —C(Me)₂OH 6.7 502.1504.1506.1 13.5 1904 4066

Cl H

7.5 627.2629.2631.0(M − H)⁻ 732 1905 4067

Cl H

5.9 516.2518.1520.1 17 1909 4068

Cl H

5.1 527.1529.1531.0(M − H)⁻ 38.5 1910 4069

Cl H

6.7 601.1603.1605.0 112 1931 4070

Cl H —C(Me)₂OH 7.1 536.0538.0540.0 82.5 1933 4071

Cl H

5.6 558.1560.1562.0 8.75 1934 4072

Cl H

4.7 499.0501.0503.0(M − H)⁻ 38.5 1935 4073

Cl H

6.6 532.1534.1536.0 51 1945 4074

Cl H —C(Me)₂OMe 6.4 516.1518.1520.0 35.5 1950 4075

Cl H

5.8 572.1574.1576.0 20.5 1952 4076

Cl H

5.8 578.9581.9583 17.5 1960 4077

Cl H —C(Me)₂COOMe 7.3 572.0574.0576.0 44.5 1962 4078

Br H —C(Me)₂OH 6.5 546.0548.0550.0 13.5 1978 4079

Cl H

5.9 569.1572.1574.0 6.8 1979 4080

Cl H

5.6 543.1545.1547.0 8.45 1980 4081

Cl H

6.1 573.1575.1577.0 19.5 1987 4082

Cl H

5.5 599.0601.0603.0 80 1989 4083

Cl H

5.6 514.0516.0518.0 29 1999 4084

Cl H

5.6 528.0530.0532 43 2000 4085

Cl H

5.2 606.0608.0610.0 12 2001 4086

Cl H

5.6 622.0624.0626.0 12 2002 4087

Cl H

5.0 586.0588.0590.0 21.5 2003 4088

Cl H —COOH 5.8 504.0506.0508.0 38.5 2007 4089

Cl H —H 6.4 460.0462.0464.0 69 2009 4090

Cl H

6.5 558.0560.0562.0 23 2010 4091

Cl H —CH₂OH 5.3 474.0476.0478.0 20.5 2015 4092

Cl H

5.2 567.1569.1571.1 61.5 2017 4093

Cl H —COOH 5.3 488.0490.0492.0 47 2026 4094

Cl H

4.6 596.2598.2600 48.5 2027 4095

Cl H

4.5 610.2612.2614.0 98.5 2028 4096

Cl H

4.9 597.1599.1601.0 37 2031 4097

Cl H H 5.9 444.1446.0448.0 44 2033 4098

Cl H

5.7 544.1546.1548.0(M − H)⁻ 16.5 2034 4099

Cl H —C(Me)₂COOH 6.9 574.0576.0578.0(M − H)⁻ 42.5 2040 4100

Cl F —C(Me)₂COOH 6.7 548.1550.1552.0 18 2041 4101

Cl F —C(Me)₂COOH 6.6 575.9577.9579.0 57 2046 4102

Cl H —(CH₂)₂COOH 5.9 532.1534.1536.0 24.5 2053 4103

Cl H

5.5 613.2615.2617.0 218 2054 4104

Cl H

5.2 629.2631.2633.0 64.5 2055 4105

Cl H

4.7 628.2630.2632.0 66.5 2056 4106

Cl H

6.2 605.1607.1609.0 19 2057 4107

Cl H

6.0 613.1615.1617.0 15 2058 4108

Cl H

5.1 614.2616.2618.0 27 2059 4109

Cl H

5.4 610.1612.1614.0 10.8 2060 4110

Cl H

5.0 612.2614.2616.2 11.5 2061 4111

Cl H

6.0 607.1609.1610.2 8.6 2064 4112

Cl H

6.8 484.1486.1488.0 54 2065 4113

Cl H

4.3 581.1583.1585.1 24.5 2068 4114

Cl H —C(Me)₂COOH 6.1 520.0522.0524.0 200 2070 4115

Cl H

5.5 626.2628.2630.0 2071 4116

Cl H

4.7 614.2616.2618.0 2072 4117

Cl H

5.2 585.2587.2589.0 52 2073 4118

Cl H

5.4 599.2601.2603.2 89.5 2074 4119

Cl H

5.4 585.1587.1589.1 121 2076 4120

Cl H

5.9 650.1652.1654.0 17.5 2077 4121

Cl H —C(Me)₂COOH 6.9 530.0532.0534.0(M − H)⁻ 33.5 2078 4122

Cl F —C(Me)₂COOH 7.1 564.1566.1568.0 15.5 2081 4123

Cl H

5.1 612.1614.1616.0 38 2082 4124

Cl H

4.6 627.1629.1631.0 27 2083 4125

Cl H

4.9 642.2644.1646.0 26 2084 4126

Cl H

5.2 720.2722.2724.0 78 2085 4127

Cl H

4.5 666.2668.2670.0 20.5 2086 4128

Cl H

5.1 553.1555.1557.1(M − H)⁻ 27 2087 4129

Cl H

4.9 598.1600.1602.1 15.5 2088 4130

Cl H

5.2 607.2609.2611.0 43 2089 4131

Cl H —(CH₂)₂OH 5.4 488.1490.1492.0 8.95 2093 4132

Cl H

4.9 541.1543.1545.0 49.5 2094 4133

Cl H

6.4 470.0472.1474.0 53.5 2095 4134

Cl H

4.6 571.1573.1575.0 28.5 2096 4135

Cl H

4.1 556.1558.1560.0 29 2102 4136

Cl H —CH₂COOH 5.3 502.1504.1506.0 32.5 2109 4137

Cl H

4.3 527.0529.0531.0(M − H)⁻ 88 2110 4138

Cl H

4.7 614.1616.1618.0 43 2111 4139

Cl H

5.8 635.1637.1639.1 20.5 2114 4140

Cl H

5.6 597.1599.1601.0 51 2115 4141

Cl H

5.3 571.1573.1575.1 40 2116 4142

Cl H

5.1 627.2629.2631.0 50.5 2117 4143

Cl H

6.6 626.2628.2630.2 65 2118 4144

Cl H

8.2 615.1617.1619.1 81 2119 4145

Cl H

6.4 614.2616.2618.2 48 2120 4146

Cl H

8.7 613.2615.2617.2 37.5 2123 4147

Cl H

5.3 642.2644.2645.2 52 2133 4148

Cl H

6.9 634.1636.1638.1(M − H)⁻ 11 2134 4149

Cl H

7.9 639.1641.1643.1(M − H)⁻ 16.5 2135 4150

Cl H

8.3 605.1607.0609.0(M − H)⁻ 19 2140 4151

Cl F

4.7 517.1519.1520.1(M − H)⁻ 22.5 2149 4152

Cl H

7.8 654.2656.2658.2 36.5 2150 4153

Cl H

6.77 662.2664.2666.2 127 2153 4154

Cl H

4.9 670.1672.1674.0 10.5 2155 4155

Cl F

5.0 604.1606.1608.0 9.15 2156 4156

Cl F

5.13 632.2634.2636.0 36.5 2157 4157

Cl F

5.6 640.1642.1644.0 5.95 2158 4158

Cl H —C(Me)₂COOH 7.0 598.1600.1602.0 208.5 2159 4159

Cl H —C(Me)₂COOH 7.0 598.1600.1602.1 136.5 2161 4160

Cl F

5.6 672.1674.1676.0 114 2167 4161

Cl H —C(Me)₂COOH 6.3 524.0526.0528.0 223.5 2168 4162

Cl H —C(Me)₂COOH 6.3 524.0526.0528.0529.0 99 2170 4163

Cl F

4.4 545.1547.1549.0(M − H)⁻ 83 2171 4164

Cl F

5.4 668.1670.1672.1 18.5 2172 4165

Cl F

5.5 641.2643.2645.0 67.5 2173 4166

Cl F

5.4 669.2671.2673.0 126 2174 4167

Cl H

5.4 623.2625.2627.0 39.5 2175 4168

Cl H

5.3 651.2653.2655.0 107.5 2176 4169

Cl F

5.8 562.1564.1566.0(M − H)⁻ 9.2 2178 4170

Cl F

4.8 660.2662.2664.0 33.5 2179 4171

Cl F

4.8 632.2634.2636.0 31.5 2180 4172

Cl H —C(Me)₂COOH 5.7 602.2604.2606.0 578.5 2181 4173

Cl H —C(Me)₂COOH 9.0 544.2546.1548.2 51 2184 4174

Cl H —C(Me)₂COOH 6.6 530.1532.1534.1 34 2186 4175

Cl F

5.5 617.2619.2621.1 67 2187 4176

Cl F

4.7 632.2634.2636.0 108 2190 4177

Cl F

4.9 571.1573.1575.0(M − H)⁻ 23 2191 4178

CH₃ F

5.8 620.2622.2624.0 26 2192 4179

Cl H —C(Me)₂COOH 6.5 530.1532.1534.0 467.5 2193 4180

CH₃ H

5.7 602.2604.2606.0 71 2194 4181

Cl H —C(Me)₂CH₂COOH 5.8 544.1546.1548.0 26.5 2195 4182

Cl H

6.8 613.2615.2617.0 58.5 2196 4183

Cl H

9.3 669.1671.1673.1 61 2197 4184

Cl H

8.8 631.1633.1635.1(M − H)⁻ 30.5 2198 4185

Cl H

8.9 636.1638.1640.1 55.5 2203 4186

Cl H

4.7 608.2610.2612.0 12 2205 4187

Cl H —C(Me)₂COOH 6.7 548.1550.1552.0 61.5 2210 4188

Cl H

5.1 635.2637.2639.0 24 2213 4189

Cl H

5.7 616.1618.1620.1 19.5 2214 4190

Cl H

5.5 545.2547.2549.0 59.5 2215 4191

Cl H

6.0 622.2624.2626.0 4.75 2216 4192

Cl H

4.7 558.2560.2562.0 7.9 2217 4193

Cl H

5.1 651.2653.2655.0 29 2218 4194

Cl H

4.7 621.1623.1625.1626.1 45 2219 4195

Cl H

5.0 627.2629.2631.0 22.5 2224 4196

Cl H —C(Me)₂COOH 7.3 558.1560.1562.1 198 2225 4197

Cl H

8.6 619.1621.1623.1(M − H)⁻ 57.5 2227 4198

Cl F

4.8 645.2647.2649.2 22 2228 4199

Cl H —C(Me)₂OH 8.6 518.1520.1522.0 32 2229 4200

Cl H —C(Me)₂COOH 8.8 546.1548.1550.0 35.5 2230 4201

Cl H

6.4 515.1517.1519.0(M − H)⁻ 52 2231 4202

Cl H

6.1 643.2645.2647.1 106.5 2232 4203

Cl H

6.9 667.1669.1671.0 164 2233 4204

Cl H

6.6 686.2688.2690.1 35 2234 4205

Cl H

7.6 638.1640.1642.1 28.5 2235 4206

Cl H —C(Me)₂COOH 7.0 564.1566.1568.1 152 2236 4207

Cl H —C(Me)₂COOH 5.8 490.1492.1494.0 442 2237 4208

Cl H

6.0 622.2624.1626.0 6.9 2238 4209

Cl F

4.6 632.0634.0636.0 46 2240 4210

Cl H

6.2 684.0686.0688.0 15.5 2242 4211

Cl H —C(Me)₂COOH 7.0 598.1600.1602.0 482.5 2243 4212

Cl H —C(Me)₂COOH 6.0 508.0510.0512.0 361.5 2247 4213

Cl H —C(Me)₂COOH 5.9 544.1546.0548.0 32.5 2248 4214

Cl H

5.2 558.0560.0562.0 19.5 2255 4215

Cl F

6.7 656.9658.9660.0 56.5 2256 4216

Cl F

5.9 656.9658.9660.0 41 2259 4217

Cl F

6.0 653.0655.0657.0 90.5 2261 4218

Cl H —C(Me)₂COOH 7.6 567.9569.9571.9573.0 31.5 2262 4219

Cl H —C(Me)₂COOH 9.2 624.0626.0628.0630.0 97 2263 4220

Cl H

5.6 537.0538.9540.9(M − H)⁻ 97.5 2264 4221

Cl H

6.9 593.0595.0596.9599.0(M − H)⁻ 107.5 2265 4222

Cl H

6.5 660.0662.0664.0666.0 11.5 2266 4223

Cl H

8.3 716.0718.0720.0722.0 30 2267 4224

Cl H

6.5 721.0723.0725.0727.0 101 2268 4225

Cl H

7.5 745.0747.0749.0751.0 161.5 2276 4226

Cl H

7.2 764.0766.0768.0770.0 52 2277 4227

Cl H

5.8 557.0559.0561.030.5 2284 4228

Cl H

5.3 613.1615.1617.0 30 2285 4229

Cl H

5.4 625.0627.0629.0 15 2286 4230

Cl F

6.5 708.0710.0712.0 30.5 2287 4231

Cl H

5.6 556.0558.0560.0(M − H)⁻ 16 2288 4232

Cl H

6.9 587.1589.0591.0 10 2289 4233

Cl H

7.8 613.1615.1617.0 9.35 2293 4234

Cl H

7.1 601.1603.1605.0 15.5 2294 4235

Cl H

5.4 682.1684.1686.0 718 2295 4236

Cl F

5.5 713.0715.0717.0 250 2297 4237

Cl F

5.7 570.0572.0574.0 91.5 2304 4238

Cl H

6.9 601.1603.1605.0 7.8 2305 4239

Cl H

7.1 615.1617.1619.0 8.2 2311 4240

Cl H —C(Me)₂COOH 8.7 544.1546.1548.1 174.5 2316 4241

Cl H

6.5 663.2665.2667.0 30.5 2321 4242

Cl H

7.2 703.1705.1707.0 854 2322 4243

Cl H —C(Me)₂COOH 7.4 533.1535.1537.0 140.5 2325 4244

Cl H

8.3 668.2670.2672.0 216.5 2326 4245

Cl H

6.5 628.2630.2632.0 458.5 2332 4246

Cl H

6.9 613.2615.2617.0 212.5 2333 4247

Cl H

7.4 636.2638.2640.0 19 2336 4248

Cl F

7.3 708.1710.1712.0 30.5 2337 4249

Cl H

8.3 610.1612.1614.0 202.5 2338 4250

Cl F

6.3 585.1587.1589.0(M − H)⁻ 51.5

TABLE 5

wherein R¹, R⁵ and R⁶ are given in the table below: t_(R) MS IC₅₀ BI21Cpd R¹ —N(R⁵)R⁶ (min) (MH⁺) mut (nM) 1628 5001

7.0 590.1592.1594.0 71 1629 5002

7.0 589.1591.1593.0 137 1630 5003

5.2 592.2594.2593.0 48 1631 5004

6.7 579.1581.1583.1 41 1632 5005

6.5 670.2672.2674.0 216 1633 5006

5.4 594.1596.1598.0 374 1634 5007

5.3 622.2624.2626.2 244 1635 5008

6.8 682.2684.2686.2 861 1637 5009

7.1 601.1603.1605.1 131 1638 5010

7.1 629.1631.1633.0 402 1639 5011

6.9 601.1603.1605.1 69 1640 5012

5.7 628.2630.2632.0 466 1641 5013

6.8 601.1603.1605.0 150 1642 5014

6.5 595.1597.1599.1 146 1643 5015

6.1 553.1555.1557.0 158 1644 5016

6.9 629.2631.2633.0 116 1645 5017

6.7 664.1666.1668.1 55 1646 5018

6.1 597.1599.1601.1 92 1647 5019

6.6 631.1633.1635.1 78 1648 5020

6.3 567.1569.1571.1 163 1649 5021

6.7 645.2647.1649.1 181 1650 5022

6.9 629.1631.1633.0 106 1652 5023

6.9 643.1645.1647.1 38 1653 5024

5.3 612.2614.2616.0 66 1654 5025

6.3 581.1683.1585.0 124 1655 5026

5.5 614.2616.2618.0 86 1656 5027

6.7 643.1645.1647.1 51 1657 5028

6.5 621.2623.2625.2 39 1658 5029

6.7 632.1634.1636.0 34 1659 5030

6.7 593.2595.2597.0 116 1660 5031

6.7 649.2651.2653.0 118 1932 5032

5.7 605.1607.1609.1 51.5 1972 5033

5.0 584.1566.0588.0 124.5 1973 5034

5.1 598.1600.0602.0 357 1974 5035

5.0 598.1600.1602.0 257.5 1975 5036

5.0 598.1600.1602.0 271 1976 5037

5.0 612.2614.2616.0 174 1991 5038

5.5 614.0616.0618.0 557.5 1992 5039

5.4 614.0616.0618.0 479 1993 5040

5.4 614.1616.0618.0 563 1994 5041

5.5 628.1630.0632.0 131.5

TABLE 6

wherein R¹, R⁵ and R⁶ are given in the table below: t_(R) MS IC₅₀ BI21Cpd R¹ —N(R⁵)R⁶ (min) (MH⁺) mut (nM) 1400 6001

7.2 613.1615.1617.0 69 1593 6002

6.9 519.2521.2523.0 31 1594 6003

7.1 559.2561.2563.2 13 1595 6004

5.1 562.2564.2566.0 398 1596 6005

6.9 549.2551.2553.0 564 1597 6006

6.7 640.3642.3644.0 46 1598 6007

6.2 564.2566.2568.0 30 1599 6008

5.3 570.2572.2574.0 26 1600 6009

5.9 652.3654.3656.0 73 1601 6010

7.5 570.2572.2574.0 168 1602 6011

7.2 571.2573.2575.0 26 1603 6012

5.8 598.3600.3602.0 47 1604 6013

6.9 571.2573.2575.0 34 1605 6014

7.0 599.2601.2603.0 34 1606 6015

6.6 565.2567.2569.2 39 1607 6016

—NH(CH₂)₂OH 6.1 523.2525.2527.0 35 1608 6017

6.9 599.3601.3603.0 33 1609 6018

6.0 567.2569.2571.2 28 1610 6019

6.7 601.2603.2605.2 36 1611 6020

6.7 615.3617.3619.3 51 1612 6021

7.0 599.2601.2603.0 58 1613 6022

7.0 625.2627.2629.0 14 1615 6023

5.3 584.3586.3588.0 22 1617 6024

—NH(CH₂)₂CO₂H 6.3 551.2553.2555.0 41 1618 6025

6.9 611.2613.2615.0 41 1621 6026

5.6 584.1586.1588.1 51 1622 6027

6.7 606.2608.2610.0 59 1623 6028

5.2 592.2594.2596.0 55 1624 6029

5.5 556.1558.1560.1 22 1625 6030

6.4 591.2593.2595.2 919 1893 6031

7.1 627.2629.2631.0 29.5 1894 6032

7.3 639.2641.2643.0 20.5 2037 6033

—NHC(Me)₂COOH 5.5 546.9548.9550.9 298 2050 6034

5.4 568.1570.1572.1(M − H)⁻ 44.5 2051 6035

5.4 582.1584.1586.1(M − H)⁻ 39 2067 6036

—NHSO₂CH₃ 6.5 539.0541.0543.0(M − H)⁻ 146 2090 6037

7.5 601.0603.0605.0(M − H)⁻ 111.5 2151 6038

6.1 570.1572.1574.0 64.5 2152 6039

5.9 568.1570.1572.1(M − H)⁻ 104

TABLE 7

wherein W is given in the table below: t_(R) MS IC₅₀ BI21 Cpd W (min)(MH⁺) mut (nM) 1734 7001

10.4 570.0572.0574.0 116 1735 7002

10.4 570.1572.1574.0 187 1738 7003

9.9 591.1593.0595.0 607 1739 7004

10.0 605.1607.0609.0 272 1742 7005

10.5 555.1557.1559.1 106 1743 7006

11.0 642.2644.0646.0 74 1740 7007

9.8 597.0599.0601.0 331 1748 7008

10.0 582.1584.0586.0(M − H)⁻ 428 1749 7009

9.2 612.1614.1616.0(M − H)⁻ 43 1750 7010

9.7 521.1523.1525.0 83 1812 7011

9.9 571.1573.1575.0 181 1814 7012

10.0 571.2573.2574.2 128 1815 7013

11.3 589.0591.1593.1595.0 121 1816 7014

11.5 571.2573.2575.0 415 1817 7015

11.0 599.1601.1603.0 189 1818 7016

11.0 599.2601.2603.0 145 1819 7017

11.1 614.2616.2618.0 170 1820 7018

11.1 559.2601.2603.0 100 1821 7019

11.0 614.1616.1618.0 25 1822 7020

10.3 531.2533.2533.0 69 1823 7021

11.2 547.1549.1551.0 262 1824 7022

11.6 561.1563.1565.0 629 1825 7023

11.6 561.2563.1565.0 255 1827 7024

11.5 549.2551.2553.0 414 1828 7025

11.1 612.2614.2616.2(M − H)⁻ 154 1829 7026

10.8 575.2577.2579.0 88 1830 7027

9.9 599.1601.1603.0 134 1831 7028

8.7 551.1553.1555.0 123 1835 7029

9.9 599.1601.1603.0 88 1836 7030

7.7 570.1572.1574.0 38 1837 7031

7.7 570.1572.1573.1 43 1838 7032

7.8 570.1572.1574.0 30 1912 7033

6.3 626.0628.0630.0 21.5 1913 7034

6.8 609.0611.0613.0 201 1914 7035

6.8 603.0605.0607.0609.0 100 1915 7036

6.2 637.0639.0641.0643.0 712.5 1916 7037

5.3 612.1614.0616.0 236.5 1917 7038

6.8 583.1585.0587.0 860 1918 7039

6.8 599.0601.0603.0 89.5 1919 7040

5.9 561.0563.0565.0 42.5 1920 7041

7.0 597.1599.0601.0 336.5 1924 7042

6.5 585.0587.0589.0 27 1925 7043

6.6 608.1610.0612.0 145 1928 7044

6.9 583.0585.0587.0 334.5 1930 7045

102 637.2639.0641.0 432 1942 7046

8.2 584.1586.1588.0(M − H)⁻ 140 2005 7047

7.9 586.0588.0590.0 43.5 2006 7048

7.8 586.0588.0590.0 97

1. A compound of formula (I):

wherein Ar is a tetrazole ring and wherein the groups X and R¹ areattached to positions on the Ar ring which are immediately adjacent toeach other; X is S; R¹ is a group of formula:

R¹¹ is halo; and R¹², R¹³, R¹⁴ and R¹⁵ are each independently selectedfrom H, halo, (C₁₋₄)alkyl, CF₃, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-, cyano, —O—(C₁₋₄)alkyl, —OCF₃ and—N((C₁₋₄)alkyl)₂, wherein said (C₃₋₇)cycloalkyl is optionallysubstituted with (C₁₋₄)alkyl; or R¹² and R¹³, R¹³ and R¹⁴, or R¹⁴ andR¹⁵ are linked, together with the carbon atoms to which they areattached, to form a five- or six-membered saturated, unsaturated oraromatic ring which optionally contains from one to three heteroatomseach independently selected from O, S and N, wherein the remaining ofR¹², R¹³, R¹⁴ and R¹⁵ are defined as hereinbefore; R² is halo; R³ isselected from H and halo; R⁴ is —C≡C—R⁹ wherein R⁹ is selected from: i)H, —COOH, —COO(C₁₋₆)alkyl, phenyl or (C₂₋₄)alkenyl; ii) (C₃₋₇)cycloalkyloptionally substituted with —OH, —COOH, —COO(C₁₋₆)alkyl, or (C₁₋₄)alkylwherein said (C₁₋₄)alkyl is optionally substituted with —OH or—N(R⁹¹)R⁹², wherein R⁹¹ is H and R⁹² is (C₁₋₄)alkyl substituted withHet; or R⁹¹ and R⁹², together with the N to which they are attached, arelinked together to form a 5- or 6-membered heterocycle which may besaturated, unsaturated or aromatic and which may optionally contain fromone to three further heteroatoms each independently selected from N, Oand S; said heterocycle being optionally substituted with one or twosubstituents each independently selected from (C₁₋₆)alkyl and —OH; andiii) (C₁₋₆)alkyl optionally substituted with one, two or threesubstituents each independently selected from: a) —OH, —O(C═O)NH₂,—O(C═O)NH(C₁₋₄)alkyl, CF₃, —COOH or —COO—(C₁₋₄)alkyl; b) Het optionallysubstituted with (C₁₋₆)alkyl or —OH; c) —N(R⁹³)R⁹⁴ wherein R⁹³ is H or(C₁₋₄)alkyl and R⁹⁴ is selected from H, —(C₁₋₄)alkyl optionallysubstituted with R⁹⁴¹, —SO₂-(C₁₋₄)alkyl and —C(═O)—R⁹⁴²; wherein R⁹⁴¹ is—COOH, —C(═O)NH₂, (C₃₋₇)cycloalkyl, Het, or phenyl optionallysubstituted with —OH, and R⁹⁴² is —O—(C₁₋₄)alkyl, —NH—(C₁₋₄)alkyl,phenyl, (C₃₋₇)cycloalkyl or Het, wherein said (C₃₋₇)cycloalkyl isoptionally substituted with —COOH and wherein said Het is optionallysubstituted with one or two substituents each independently selectedfrom (C₁₋₆)alkyl and —OH; or R⁹⁴² is (C₁₋₄)alkyl optionally substitutedwith —COOH, —NH₂, —NH(C₁₋₄)alkyl, —NH-Het, —N((C₁₋₄)alkyl)₂, or Het;wherein said Het is optionally substituted with one or two substituentseach independently selected from —OH, —COOH and (C₁₋₆)alkyl optionallysubstituted with Het and wherein the (C₁₋₄)alkyl portion of said—NH(C₁₋₄)alkyl is optionally substituted with Het; d) —C(═O)N(R⁹⁵)R⁹⁶,wherein R⁹⁵ is H and R⁹⁶ is selected from (C₃₋₇)cycloalkyl, —SO₂—R⁹⁶¹and —(C₁₋₄)alkyl-R⁹⁶², wherein R⁹⁶¹ is (C₁₋₄)alkyl, phenyl,(C₃₋₇)cycloalkyl, or —N((C₁₋₄)alkyl)₂; and R⁹⁶² is phenyl, —COOH,—N((C₁₋₄)alkyl)₂, or Het, wherein said phenyl is optionally substitutedwith —N((C₁₋₄)alkyl)₂ and said Het is optionally substituted with oxo;or R⁹⁵ and R⁹⁶, together with the N to which they are attached, arelinked together to form a 5- or 6-membered heterocycle which may besaturated or unsaturated and which may optionally contain from one tothree further heteroatoms each independently selected from N, O and S;said heterocycle being optionally substituted with —COOH; and e)—O(C₁₋₄)alkyl optionally substituted with R⁹⁷ wherein R⁹⁷ is selectedfrom —OH, —COOH, —C(═O)O—(C₁₋₄)alkyl-N H(C₁₋₄)alkyl, —C(═O)N(R⁹⁷¹)R⁹⁷²,—NH₂, —NH—(C₃₋₇)cycloalkyl, —O-Het, and Het; provided that the carbonatom of —O—(C₁₋₄)alkyl which is directly bonded to O is not alsodirectly bonded to —OH, —NH₂ or —NH—(C₃₋₇)cycloalkyl; wherein each ofsaid Het and the Het portion of said —O-Het is optionally substitutedwith one or two substituents each independently selected from halo, oxo,(C₁₋₄)alkyl, and —OH; and wherein R⁹⁷¹ is H or (C₁₋₄)alkyl and R⁹⁷² isselected from H, —OH, —NHC(═O)—(C₁₋₄)alkyl, —NHC(═O)—NH₂, (C₁₋₄)alkyl,(C₃₋₇)cycloalkyl, phenyl and Het, wherein said (C₁₋₄)alkyl is optionallysubstituted with —OH, —COOH, —N((C₁₋₄)alkyl)₂ or Het, provided that whenR⁹⁷² is (C₁₋₄)alkyl, the carbon atom of (C₁₋₄)alkyl which is directlybonded to N is not also directly bonded to —OH; and wherein said(C₃₋₇)cycloalkyl is optionally substituted with —COOH, and wherein saidphenyl is optionally substituted with —OH, —COOH, or—(C₂₋₄)alkenyl-COOH; or R⁹⁷¹ and R⁹⁷², together with the N to which theyare attached, are linked together to form a 5- or 6-membered heterocyclewhich may be saturated or unsaturated and which may optionally containfrom one to three further heteroatoms each independently selected fromN, O and S; said heterocycle being optionally substituted with(C₁₋₄)alkyl or —COOH; wherein Het is a 4,5- or 6-membered heterocycle ora 9- or 10-membered heterobicycle, each of which may be saturated,unsaturated or aromatic and each of which containing from one to fourheteroatoms each independently selected from N, O and S, wherein eachsaid N heteroatom may, independently and where possible, exist in anoxidized state such that it is further bonded to an O atom to form anN-oxide group and wherein each said S heteroatom may, independently andwhere possible, exist in an oxidized state such that it is furtherbonded to one or two oxygen atoms to form the groups SO or SO₂; or atautomer, salt or ester thereof.
 2. The compound according to claim 1wherein Ar is

wherein the designation

represents the bond to R¹ and the designation

represents the bond to X.
 3. The compound according to claim 1 whereinR¹¹ is chloro or bromo.
 4. The compound according to claim 1 wherein R¹²is selected from H, (C₁₋₄)alkyl, CF₃, (C₃₋₇)cycloalkyl and halo or R¹²and R¹³ are linked, together with the carbon atoms to which they areattached, to form a five- or six-membered saturated, unsaturated oraromatic ring which optionally contains from one to three heteroatomseach independently selected from O, S and N.
 5. The compound accordingto claim 4 wherein R¹² is H, CF₃ or cyclopropyl.
 6. The compoundaccording to claim 1 wherein R¹³ is selected from H, (C₁₋₄)alkyl, CF₃,(C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-, —O—(C₁₋₄)alkyl,—N((C₁₋₄)alkyl)₂ and —OCF₃; wherein the (C₃₋₇)cycloalkyl is optionallysubstituted with (C₁₋₄)alkyl; or wherein R¹² and R¹³ or R¹³ and R¹⁴ arelinked, together with the carbon atoms to which they are attached, toform a five- or six-membered saturated, unsaturated or aromatic ringwhich optionally contains from one to three heteroatoms eachindependently selected from O, S and N.
 7. The compound according toclaim 6 wherein R¹³ is H, methyl, 1,1-dimethylethyl or cyclopropyl. 8.The compound according to claim 6 wherein R¹⁴ is selected from H, halo,cyano, (C₁₋₄alkyl, CF3, (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-,—O—(C₁₋₄)alkyl, and —N((C₁₋₄)alkyl)₂ or R¹³ and R¹⁴ are linked, togetherwith the carbon atoms to which they are attached, to form a five- orsix-membered saturated, unsaturated or aromatic ring which optionallycontains from one to three heteroatoms each independently selected fromO, S and N.
 9. The compound according to claim 8 wherein R¹⁴ is H,cyclopropyl or CF₃.
 10. The compound according to claim 1 wherein R¹⁵ isselected from H, halo, (C₁₋₄)alkyl and CF₃.
 11. The compound accordingto claim 1 wherein R²is chloro.
 12. The compound according to claim 1wherein R³ is H or fluoro.
 13. The compound according to claim 1 whereinR⁴ is —C≡C—R⁹ wherein R⁹ is selected from: i) H, —COCH, —COO(C₁₋₆)alkyl,phenyl or (C₂₋₄)alkenyl; ii) (C₃₋₇)cycloalkyl optionally substitutedwith —OH, —COCH, —COO(C₁₋₆)alkyl, or (C₁₋₄)alkyl wherein said(C₁₋₄)alkyl is optionally substituted with —OH or —N(R⁹¹)R⁹², whereinR⁹¹ is H and R⁹² is (C₁₋₄)alkyl substituted with Het; or R⁹¹ and R⁹²,together with the N to which they are attached, are linked together toform a 5- or 6-membered heterocycle which may be saturated, unsaturatedor aromatic and which may optionally contain from one to three furtherheteroatoms each independently selected from N, O and S; saidheterocycle being optionally substituted with one or two substituentseach independently selected from (C₁₋₆)alkyl and —OH; and iii)(C₁₋₆)alkyl optionally substituted with one, two or three substituentseach independently selected from: a) —OH, —O(C═O)NH₂,—O(C═O)NH(C₁₋₄)alkyl, CF₃, —COOH or —COO—(C₁₋₄)alkyl; b) Het optionallysubstituted with (C₁₋₆)alkyl or —OH; c) —N(R⁹³)R⁹⁴ wherein R⁹³ is H or(C₁₋₄)alkyl and R⁹⁴ is selected from H, —(C¹⁻⁴)alkyl optionallysubstituted with R⁹⁴¹, —SO₂—(C₁₋₄)alkyl and —C(═O)—R⁹⁴²; wherein R⁹⁴¹ is—COOH, —C(═O)NH₂, (C₃₋₇)cycloalkyl, Het, or phenyl optionallysubstituted with —OH, and R⁹⁴² is —O—(C¹⁻⁴)alkyl, —NH—(C₁₋₄)alkyl,phenyl, (C₃₋₇)cycloalkyl or Het, wherein said (C₃₋₇)cycloalkyl isoptionally substituted with —COOH and wherein said Het is optionallysubstituted with one or two substituents each independently selectedfrom (C₁₋₆)alkyl and —OH; or R⁹⁴² is (C₁₋₄)alkyl optionally substitutedwith —COOH, —NH₂, —NH(C₁₋₄)alkyl, —NH-Het, —N((C₁₋₄alkyl)₂, or Het;wherein said Het is optionally substituted with one or two substituentseach independently selected from —OH, —COOH and (C₁₋₆)alkyl optionallysubstituted with Het and wherein the (C₁₋₄)alkyl portion of said—NH(C₁₋₄)alkyl is optionally substituted with Het; d) —C(═O)N(R⁹⁵)R⁹⁶,wherein R⁹⁵ is H and R⁹⁶ is selected from (C₃₋₇)cycloalkyl, —SO₂—R⁹⁶¹and —(C₁₋₄)alkyl—R⁹⁶², wherein R961 is (C₁₋₄)alkyl, phenyl,(C₃₋₇)cycloalkyl, or —N((C₁₋₄)alkyl)₂; and R962 is phenyl, —COCH,—N((C₁₋₄)alkyl)₂, or Het, wherein said phenyl is optionally substitutedwith —N((C₁₋₄)alkyl)₂ and said Het is optionally substituted with oxo;or R⁹⁵ and R^(96,) together with the N to which they are attached, arelinked together to form a 5- or 6-membered heterocycle which may besaturated or unsaturated and which may optionally contain from one tothree further heteroatoms each independently selected from N, O and S;said heterocycle being optionally substituted with —COCH; and e)—O(C₁₋₄)alkyl optionally substituted with R⁹⁷ wherein R⁹⁷ is selectedfrom —OH, —COCH, —C(═O)O—(C₁₋₄)alkyl-NH(C₁₋₄)alkyl, —C(═O)N(R⁹⁷¹)R⁹⁷²,—NH², —NH—(C₃₋₇)cycloalkyl, -13 O-Het, and Het; provided that the carbonatom of O—(C₁₋₄)alkyl which is directly bonded to O is not also directlybonded to —OH, —NH₂ or —NH—(C₃₋₇)cycloalkyl; wherein each of said Hetand the Het portion of said —O-Het is optionally substituted with one ortwo substituents each independently selected from halo, oxo,(C₁₋₄)alkyl, and —OH; and wherein R⁹⁷¹ is H or (C₁₋₄)alkyl and R⁹⁷² isselected from H, —OH, —NHC(═O)—(C¹⁻⁴)alkyl, —NHC(═O)—NH₂, (C₁₋₄)alkyl,(C₃₋₇)cycloalkyl, phenyl and Het, wherein said (C₁₋₄)alkyl is optionallysubstituted with —OH, —COOH, —N((C₁₋₄)alkyl)₂ or Het, provided that whenR⁹⁷² is (C₁₋₄)alkyl, the carbon atom of (C₁₋₄)alkyl which is directlybonded to N is not also directly bonded to —OH; and wherein said(C₃₋₇)cycloalkyl is optionally substituted with —COOH, and wherein saidphenyl is optionally substituted with —OH, —COOH, or—(C₂₋₄)alkenyl-COOH; or R⁹⁷¹ and R⁹⁷², together with the N to which theyare attached, are linked together to form a 5- or 6-membered heterocyclewhich may be saturated or unsaturated and which may optionally containfrom one to three further heteroatoms each independently selected fromN, O and S; said heterocycle being optionally substituted with(C₁₋₄)alkyl or —-COCH; wherein Het is in each instance independently a4, 5- or 6-membered saturated, unsaturated or aromatic monocyclicheterocycle containing from one to four heteroatoms each independentlyselected from N, O and S, wherein each said N heteroatom may,independently and where possible, exist in an oxidized state such thatit is further bonded to an atom to form an N-oxide group and whereineach said S heteroatom may, independently and where possible, exist inan oxidized state such that it is further bonded to one or two oxygenatoms to form the groups SO or SO².
 14. The compound according to claim13 wherein R⁹ is selected from: i) H, —COCH, phenyl, ethenyl or2-propenyl; ii) cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, eachof which being optionally substituted with —OH, —COCH or CH₃, whereinsaid CH₃ is optionally substituted with OH or -N(R⁹¹)R⁹², wherein R⁹¹ isH and R⁹² is

or R⁹¹ and R^(92,) together with the N to which they are attached, arelinked together to form a 5- or 6-membered heterocycle which may besaturated, unsaturated or aromatic and which may optionally contain oneor two further heteroatoms each independently selected from N and O;said heterocycle being optionally substituted with one or twosubstituents each independently selected from CH₃ and —OH; iii) methyl,ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl,1,1-dimethylethyl, pentyl or 1-ethylpropyl, each of which beingoptionally substituted with one, two or three substituents eachindependently selected from: a) —OH, —O(C═O)NH₂, —O(C═O)NHCH₃, CF₃,—COOH, —COOCH₃ or COOCH₂CH₃; b) Het optionally substituted with CH₃ or—OH; wherein Het is selected from

c) —N(R⁹³)R⁹⁴ wherein R⁹³ is H, CH₃ or CH₂CH₃ and R⁹⁴ is selected fromH, —(C₁₋₄)alkyl optionally substituted with R⁹⁴¹, —SO₂-CH₃ and—C(═O)—R⁹⁴²; wherein R⁹⁴¹ is COCH, —C(═O)NH₂, cyclopropyl, Het, orphenyl optionally substituted with —OH; wherein Het is selected from

and R⁹⁴² is —O—(C₁₋₄)alkyl, —NH—(C₁₋₄)alkyl, phenyl, cyclopropyl or Het;wherein Het is selected from

and wherein said cyclopropyl is optionally substituted with —COCH andwherein said Het is optionally substituted with CH₃ or —OH; or R⁹⁴² is(C₁₋₄)alkyl optionally substituted with —COCH, —NH₂, —NH(C₁₋₄)alkyl,

—N(C₁₋₄)alkyl₂, or Het; wherein Het is selected from

and wherein said Het is optionally substituted with one or twosubstituents each independently selected from —OH, —COCH and (C₁₋₄)alkyloptionally substituted with

and wherein the (C₁₋₄)alkyl portion of said —NH(C₁₋₄)alkyl is optionallysubstituted with

d) —C(═O)N(R⁹⁵)R⁹⁶ , wherein R⁹⁵ is H and R⁹⁶ is selected fromcyclopropyl, —SO₂—R₉₆₁ and —(C₁₋₄)alkyl—R⁹⁶², wherein R⁹⁶¹ is CH₃,CH₂CH₃, phenyl, cyclopropyl, or —N(CH₃)₂; and R⁹⁶² is phenyl, —COCH,—N(CH₃)₂, or Het; wherein Het is selected from

and wherein said phenyl is optionally substituted with —N(CH₃)₂ and saidHet is optionally substituted with oxo; or R⁹⁵ and R⁹⁶, together withthe N to which they are attached, are linked together to form a6-membered heterocycle which may be saturated or unsaturated and whichmay optionally contain one or two further heteroatoms each independentlyselected from N and O; said heterocycle being optionally substitutedwith COCH; and e) —O(C₁₋₄)alkyl optionally substituted with R⁹⁷ whereinR⁹⁷ is selected from —OH, —COCH, —C(═O)O—CH₂CH₂—NHCH₃,—C(═O)N(R⁹⁷¹)R⁹⁷², —NH₂, —NH—(C₃₋₇)cycloalkyl,

and Het; provided that the carbon atom of O—(C₁₋₄)alkyl which isdirectly bonded to O is not also directly bonded to —OH, —NH₂ or—NH—(C₃₋₇)cycloalkyl; wherein Het is selected from

and wherein said Het is optionally substituted with one or twosubstituents each independently selected from halo, oxo, OH3 and OH; andwherein R⁹⁷¹ is H or CH₃ and R⁹⁷² is selected from H, —OH, —NHC(═O)—CH₃,—NHC(═O)—NH₂, (C₁₋₄)alkyl, cyclopropyl, phenyl and Het; wherein Het isselected from

and wherein said (C₁₋₄)alkyl is optionally substituted with —OH, —COCH,—N(CH₃)₂ or

provided that when R⁹⁷² is (C₁₋₄)alkyl, the carbon atom of (C₁₋₄)alkylwhich is directly bonded to N is not also directly bonded to —OH; andwherein said cyclopropyl is optionally substituted with —COCH, andwherein said phenyl is optionally substituted with —OH, —COCH, or—CH═CH—COOH; or R⁹⁷¹ and R⁹⁷², together with the N to which they areattached, are linked together to form a 5- or 6-membered heterocyclewhich may be saturated or unsaturated and which may optionally containone or two further heteroatoms each independently selected from N and O;said heterocycle being optionally substituted with OH₃ or —COCH.
 15. Acompound of formula (I):

wherein Ar is a tetrazole ring and wherein the groups X and R¹ areattached to positions on the Ar ring which are immediately adjacent toeach other; X is S; R¹ is a group of formula:

R¹¹ is halo; and R¹², R¹³, R¹⁴ and R¹⁵ are each independently selectedfrom H, halo, (C₁₋₄)alkyl, CF₃, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl-(C₁₋₄)alkyl-, cyano, —O—(C₁₋₄)alkyl, —OCF₃ and—N((C₁₋₄alkyl)₂, wherein said (C₃₋₇)cycloalkyl is optionally substitutedwith (C₁₋₄)alkyl; or R¹² and R¹³, R¹³ and R¹⁴, or R¹⁴ and R¹⁵ arelinked, together with the carbon atoms to which they are attached, toform a five- or six-membered saturated, unsaturated or aromatic ringwhich optionally contains from one to three heteroatoms eachindependently selected from O, S and N, wherein the remaining of R¹²,R¹³, R¹⁴ and R¹⁵ are defined as hereinbefore; R² is halo; R³ is selectedfrom H and halo; R⁴ is —C≡C—R⁹ wherein R⁹ is selected from: i) H, —COCH,—COO(C₁₋₆)alkyl, phenyl or (C₂₋₄)alkenyl; ii) (C₃₋₇)cycloalkyloptionally substituted with —OH, —COCH, —COO(C₁₋₆)alkyl, or (C₁₋₄alkylwherein said (C₁₋₄)alkyl is optionally substituted with OH or—N(R⁹¹)R⁹², wherein R⁹¹ is H and R⁹² is (C₁₋₄)alkyl substituted withHet; or R⁹¹ and R⁹², together with the N to which they are attached, arelinked together to form a 5- or 6-membered heterocycle which may besaturated, unsaturated or aromatic and which may optionally contain fromone to three further heteroatoms each independently selected from N, Oand S; said heterocycle being optionally substituted with one or twosubstituents each independently selected from (C₁₋₆)alkyl and —OH; andiii) (C₁₋₆)alkyl optionally substituted with one, two or threesubstituents each independently selected from: a) —OH, —O(C═O)NH₂,—O(C═O)NH(C₁₋₄)alkyl, CF₃, —COOH or —COO—(C₁₋₄)alkyl; b) Het optionallysubstituted with (C₁₋₆)alkyl or —OH; c) —N(R⁹³)R⁹⁴ wherein R⁹³ is H or(C¹⁻⁴)alkyl and R⁹⁴ is selected from H, —(C₁₋₄)alkyl optionallysubstituted with R⁹⁴¹, —SO₂—(C₁₋₄)alkyl and —C(═O)—R⁹⁴²; wherein R⁹⁴¹ is—COOH, —C(═O)NH₂, (C₃₋₇)cycloalkyl, Het, or phenyl optionallysubstituted with —OH, and R⁹⁴² is —O—(C₁₋₄)alkyl, —NH—(C₁₋₄)alkyl,phenyl, (C₃₋₇)cycloalkyl or Het, wherein said (C₃₋₇)cycloalkyl isoptionally substituted with —COOH and wherein said Het is optionallysubstituted with one or two substituents each independently selectedfrom (C₁₋₆)alkyl and —OH; or R⁹⁴² is (C₁₋₄)alkyl optionally substitutedwith COCH, —NH₂, —NH(C₁₋₄)alkyl, —NH-Het, —N((C₁₋₄)alkyl)₂, or Het;wherein said Het is optionally substituted with one or two substituentseach independently selected from —OH, —COCH and (C₁₋₆)alkyl optionallysubstituted with Het and wherein the (C₁₋₄)alkyl portion of said—NH(C₁₋₄)alkyl is optionally substituted with Het; d) —C(═O)N(R⁹⁵)R⁹⁶,wherein R⁹⁵ is H and R⁹⁶ is selected from (C³⁻⁷)cycloalkyl, —SO₂—R⁹⁶¹and —(C₁₋₄)alkyl-R⁹⁶², wherein R⁹⁶¹ is (C₁₋₄)alkyl, phenyl,(C₃₋₇)cycloalkyl, or —N((C₁₋₄)alkyl)₂; and R962 is phenyl, COCH,—N((C₁₋₄)alkyl)₂, or Het, wherein said phenyl is optionally substitutedwith —N((C₁₋₄)alkyl)₂ and said Het is optionally substituted with oxo;or R⁹⁵ and R⁹⁶, together with the N to which they are attached, arelinked together to form a 5- or 6-membered heterocycle which may besaturated or unsaturated and which may optionally contain from one tothree further heteroatoms each independently selected from N, O and S;said heterocycle being optionally substituted with —COCH; and e)—O(C₁₋₄)alkyl optionally substituted with R⁹⁷ wherein R⁹⁷ is selectedfrom —OH, —COCH, —C(═O)O—(C₁₋₄)alkyl-NH(C₁₋₄)alkyl, —C(═O)N(R⁹⁷¹)R⁹⁷²,—NH₂, —NH—(C₃₋₇)cycloalkyl, O-Het, and Het wherein said Het isoptionally substituted with one or two substituents each independentlyselected from halo, oxo, (C₁₋₄)alkyl, and —OH; wherein R⁹⁷¹ is H or(C₁₋₄)alkyl and R⁹⁷² is selected from H, —OH, —NHC(═O)—(C₁₋₄)alkyl,—NHC(═O)—NH₂, (C₁₋₄)alkyl, (C₃₋₇)cycloalkyl, phenyl and Het, whereinsaid (C₁₋₄)alkyl)₂ is optionally substituted with —OH, —COOH,—N((C₁₋₄)alkyl)₂ or Het, and wherein said (C₃₋₇cycloalkyl is optionallysubstituted with —COOH, and wherein said phenyl is optionallysubstituted with —OH, —COOH, or —(C₂₋₄)alkenyl-COOH; or R⁹⁷¹ and R₉₇₂,together with the N to which they are attached, are linked together toform a 5- or 6-membered heterocycle which may be saturated orunsaturated and which may optionally contain from one to three furtherheteroatoms each independently selected from N, O and S; saidheterocycle being optionally substituted with (C₁₋₄)alkyl or —COCH;wherein Het is a 5- or 6-membered heterocycle or a 9- or 10-memberedheterobicycle, each of which may be saturated, unsaturated or aromaticand each of which may optionally contain from one to four heteroatomseach independently selected from N, O and S, wherein each said Nheteroatom may, independently and where possible, exist in an oxidizedstate such that it is further bonded to an O atom to form an N-oxidegroup and wherein each said S heteroatom may, independently and wherepossible, exist in an oxidized state such that it is further bonded toone or two oxygen atoms to form the groups SO or SO₂; or a tautomer orpharmaceutically acceptable salt or ester thereof.
 16. A pharmaceuticalcomposition, comprising a compound according to claim 1, or apharmaceutically acceptable salt or ester thereof, and apharmaceutically acceptable carrier.